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Biomedical subjects

J Leon

Publications and source records attributed to J Leon.

At least 19 recordsLinked to original sources
PubMed2006

Comprehensive DNA methylation profiling in a human cancer genome identifies novel epigenetic targets.

Using a unique microarray platform for cytosine methylation profiling, the DNA methylation landscape of the human genome was monitored at more than 21,000 sites, including 79% of the annotated transcriptional start sites (TSS). Analysis of an oligodendroglioma derived cell line LN-18 revealed more than 4000 methylated TSS. The gene-centric analysis indicated a complex pattern of DNA methylation exists along each autosome, with a trend of increasing density approaching the telomeres. Remarkably, 2% of CpG islands (CGI) were densely methylated, and 17% had significant levels of 5 mC, whether or not they corresponded to a TSS. Substantial independent verification, obtained from 95 loci, suggested that this approach is capable of large scale detection of cytosine methylation with an accuracy approaching 90%. In addition, we detected large genomic domains that are also susceptible to DNA methylation reinforced inactivation, such as the HOX cluster on chromosome 7 (CH7). Extrapolation from the data suggests that more than 2000 genomic loci may be susceptible to methylation and associated inactivation, and most have yet to be identified. Finally, we report six new targets of epigenetic inactivation (IRX3, WNT10A, WNT6, RARalpha, BMP7 and ZGPAT). These targets displayed cell line and tumor specific differential methylation when compared with normal brain samples, suggesting they may have utility as biomarkers. Uniquely, hypermethylation of the CGI within an IRX3 exon was correlated with over-expression of IRX3 in tumor tissues and cell lines relative to normal brain samples.

Brain↗
PubMed2005

Bistability in the sine-Gordon equation: the ideal switch.

The sine-Gordon equation, used as the representative nonlinear wave equation, presents a bistable behavior resulting from nonlinearity and generating hysteresis properties. We show that the process can be understood in a comprehensive analytical formulation and that it is a generic property of nonlinear systems possessing a natural band gap. The approach allows one to discover that the sine-Gordon equation can work as an ideal switch by reaching a transmissive regime with vanishing driving amplitude.

Journal Article↗
PubMed2003

Neurally-mediated and neurally-independent beneficial actions of melatonin in the gastrointestinal tract.

Melatonin (N-acetyl-5-methoxytryptamine), originally discovered in the pineal gland, is now known also to be present in the gastrointestinal tract from the stomach to the colon. It is localized and likely synthesized in the enterochromaffin cells of the mucosal lining. Its functions in the gut generally seem to be protective of the mucosa from erosion and ulcer formation and to possibly influence movement of the gastrointestinal contents through the digestive system. In this brief review, we summarize the work documenting the function of melatonin in influencing bicarbonate secretion in the stomach and its role in preventing and repairing ulcers in the stomach and duodenum. Melatonin's actions in the control of bicarbonate secretion involve the central and peripheral sympathetic nervous systems and the actions are receptor mediated. Conversely, melatonin's actions in reducing ulcer formation also seemingly involve the ability of the indole to directly scavenge toxic oxygen-based reactants, e.g., the hydroxyl radical, and possibly to promote antioxidative enzyme activities. These same processes may be involved in the mechanisms by which melatonin promotes ulcer healing. Additionally, however, melatonin's effects on the healing of ulcers includes actions of blood flow in the margins of the ulcer and also on the sensory nerves. All indications are that melatonin has a variety of beneficial effects in the gastrointestinal tract. It is likely, however, that additional actions of melatonin on the digestive system will be uncovered.

Animals↗
PubMed2002

Energy transmission in the forbidden band gap of a nonlinear chain.

A nonlinear chain driven by one end may propagate energy in the forbidden band gap by means of nonlinear modes. For harmonic driving at a given frequency, the process occurs at a threshold amplitude by sudden large energy flow that we call nonlinear supratransmission. The bifurcation of energy transmission is demonstrated numerically and experimentally on the chain of coupled pendula (sine-Gordon and nonlinear Klein-Gordon equations) and sustained by an extremely simple theory.

Journal Article↗
PubMed2001

Cell growth inhibition by the multifunctional multivalent zinc-finger factor CTCF.

The 11-zinc finger protein CCTC-binding factor (CTCF) employs different sets of zinc fingers to form distinct complexes with varying CTCF- target sequences (CTSs) that mediate the repression or activation of gene expression and the creation of hormone-responsive gene silencers and of diverse vertebrate enhancer-blocking elements (chromatin insulators). To determine how these varying effects would integrate in vivo, we engineered a variety of expression systems to study effects of CTCF on cell growth. Here we show that ectopic expression of CTCF in many cell types inhibits cell clonogenicity by causing profound growth retardation without apoptosis. In asynchronous cultures, the cell-cycle profile of CTCF-expressing cells remained unaltered, which suggested that progression through the cycle was slowed at multiple points. Although conditionally induced CTCF caused the S-phase block, CTCF can also arrest cell division. Viable CTCF-expressing cells could be maintained without dividing for several days. While MYC is the well-characterized CTCF target, the inhibitory effects of CTCF on cell growth could not be ascribed solely to repression of MYC, suggesting that additional CTS-driven genes involved in growth-regulatory circuits, such as p19ARF, are likely to contribute to CTCF-induced growth arrest. These findings indicate that CTCF may regulate cell-cycle progression at multiple steps within the cycle, and add to the growing evidence for the function of CTCF as a tumor suppressor gene.

3T3 Cells↗
PubMed1999

Cost-effectiveness of donepezil in the treatment of mild or moderate Alzheimer's disease.

OBJECTIVE: To demonstrate the use of cost-effectiveness analysis to assess the economic impact of donepezil in the treatment of mild or moderate AD. BACKGROUND: Cost-effectiveness analyses show the relationship between resources used (costs) and health benefits achieved (effects) for an intervention compared with an alternative strategy. METHODS: We developed a model to estimate the incremental cost-effectiveness of donepezil compared with no treatment. We determined costs per quality-adjusted life-years gained, a measurement that enhances the comparability of diverse studies. The model projects the progression of AD patients into more severe disease stages and into nursing homes. Data from a randomized clinical trial of donepezil were used to assess the drug's impact on the 6-week probabilities of progression. Data on the costs and health-related quality of life associated with different disease stages and settings were taken from published estimates and our companion cross-sectional study, respectively. RESULTS: Donepezil costs are partially offset by a reduction in the costs of care due to enhancement in cognitive functioning and the delay to more costly disease stages and settings. The magnitude of this cost offset and of the effect of donepezil on health-related quality of life depends on the model's assumptions about the duration of the drug effect, where controlled data are lacking. If the drug effect exceeds 2 years, the model predicts that for mild AD the drug would pay for itself in terms of cost offsets. CONCLUSIONS: The results of the cost-effectiveness model presented here suggest that donepezil may be cost-effective but additional controlled data on long-term drug efficacy are needed.

Alzheimer Disease↗
PubMed1999

Novel cross-reactive anti-idiotype antibodies with properties close to the human intravenous immunoglobulin (IVIg).

The most important link between the immune network theory and clinically useful therapies so far is the use of human intravenous immunoglobulin (IVIg) in the treatment of autoimmune diseases. Although still controversial, one of the main mechanisms that has been postulated for the in vivo effects of IVIg, is the selection of immune repertoires through idiotypic interactions. We describe here anti-idiotype IgG monoclonal antibodies (MAbs), which were obtained by immunization of syngeneic mice (Balb/c) with an anti-ganglioside antibody. These anti-idiotype MAbs show multiple idiotypic connections and share some of the properties of the IVIg pool. The antiidiotype (Ab2) MAbs B7 and 34B7 showed heterogeneous binding with the idiotypes of several anti-ganglioside antibodies, MAbs obtained from splenocytes of nonimmunized newborn mice, F(ab')2 fragments of IgG human myeloma proteins, and nonimmunoglobulin antigens. The recognition pattern of the B7 MAb to the idiotypes of human immunoglobulins was also studied using a phage display library obtained from the variable region genes of an asymptomatic AIDS patient and also F(ab')2 fragments obtained from an IVIg pool of healthy human donors. We also demonstrated that these MAbs produced some of the in vitro effects reported for the human IVIg pool, such as the inhibition of cell proliferation of human B and T cell lines and of normal human lymphocytes activated with different mitogens. Another striking property of the MAb B7 was its ability to induce a dose-dependent specific antibody T-cell response in vivo in syngeneic mice. Both anti-idiotype MAbs showed anti-metastatic effect in vivo when injected intravenously to mice inoculated with MB16-F10 melanoma cells. The antimetastatic effect of the antiidiotype MAbs was not observed in athymic mice inoculated with the same tumor. This kind of antibody can become an interesting tool for further exploration of the role of idiotypic network connections in the regulation of the immune system and to study the effects of interventions on network connectivity in experimental autoimmune disease, using a reagent better chemically defined than the IVIg pool.

Animals↗
PubMed1999

Potential cost savings in residential care for Alzheimer's disease patients.

Data from a 1996 cross-sectional study examining the costs of care for Alzheimer's Disease patients are used to estimate the potential cost savings that could result by substituting assisted living for nursing home care for AD residents with health profiles that appear to be manageable within assisted living facilities that specialize in dementia care. Results indicate that up to 13.9% of nursing home costs could be saved, making such a service substitution an attractive alternative in the provision of residential care for certain categories of AD patients.

Aged↗
PubMed1999

Health utilities in Alzheimer's disease: a cross-sectional study of patients and caregivers.

OBJECTIVES: Although the broad impacts of Alzheimer's disease (AD) are increasingly recognized, little work has focused on the overall health-related quality of life experienced by Alzheimer's disease patients and their caregivers. The study had two main objectives: (1) to test the feasibility of measuring health utilities in Alzheimer's disease with a generic preference-weighted instrument using proxy respondents and (2) to assess the utility scores of Alzheimer's disease patients (and their caregivers) in different disease stages and care setting. METHODS: A cross-sectional study of 679 Alzheimer's disease patient/caregiver pairs was conducted at 13 sites in the United States: four academic medical centers, four managed care plans, two assisted living facilities, and three nursing homes. The Health Utilities Index Mark II (HUI:2) questionnaire was administered to caregivers of patients who responded both as proxies for patients and for themselves. Responses to the questionnaire were converted into a global utility score, between 0 and 1, using the HUI:2 multi-attribute utility function. RESULTS: Global utility scores varied considerably across patients' Alzheimer's disease stage: for the six stages assessed (questionable, mild, moderate, severe, profound, and terminal), mean utility scores were 0.73, 0.69, 0.53, 0.38, 0.27, and 0.14, respectively. In multiple regression analyses, Alzheimer's disease stage was a negative and significant predictor of utility scores for patients; setting did not exert an independent effect. Utility scores for the caregivers were insensitive to patients' Alzheimer's disease stage and setting. CONCLUSIONS: Patients' Alzheimer's disease stage had a substantial influence on health utilities, as measured by the HUI:2. More research is needed to assess the validity of using proxy respondents.

Activities of Daily Living↗
PubMed1999

Cartilage and serum levels of nitric oxide in patients with hip osteoarthritis.

OBJECTIVE: To assess whether nitric oxide (NO) is related to cartilage deterioration resulting from osteoarthritis, NO concentrations were analyzed in normal and deteriorated areas of cartilage obtained from femur heads of patients with primary hip osteoarthritis (HOA). METHODS: The concentration of NO in macroscopically deteriorated and non-deteriorated cartilage of femoral heads of patients with HOA at hip replacement surgery was analyzed spectrophotometrically. Serum NO levels were also determined in 16 ambulatory patients with hip OA and in healthy volunteers. RESULTS: NO levels of non-deteriorated areas of femoral head cartilage were significantly lower (3.82+/-1.30 micromol/l; mean +/- SD) than levels of deteriorated cartilage areas (11.07+/-6.48 micromol/l; p<0.01). The surgery HOA group showed serum NO levels (2.64+/-0.32 micromol/l; p<0.0001 vs. healthy group) similar to the ambulatory HOA group levels (2.56+/-0.56 micromol/l; p<0.0001 vs. healthy group). Serum NO concentrations in healthy volunteers were 1.37+/-0.55 micromol/l. CONCLUSION: This study shows increased NO levels in joint cartilage of patients with hip OA. This increase was not homogeneously distributed, but the higher NO levels were found in macroscopically deteriorated areas. The data also suggest that high NO serum levels found in patients with hip OA may be due to joint cartilage destruction.

Aged↗
PubMed1999

The cost of Alzheimer's disease in managed care: a cross-sectional study.

BACKGROUND: The number of people with Alzheimer's disease (AD) is expected to grow as the US population ages. Given the increasing enrollment in managed care organizations, growth in the number of managed care patients with AD is a certainty. To our knowledge, no study to date has focused on the cost of care of community-dwelling AD patients receiving care through a health maintenance organization (HMO) system. METHODS: One hundred and fifty patients were recruited from 4 managed care sites from July through December 1996. Staff at each site clinically confirmed patients' AD diagnosis, AD severity, and ascertained patients' comorbidities. Demographic, quality of life, and service utilization data were collected from proxy respondents. Costs of hospitalization, medications, doctor visits (formal costs), and caregiver assistance (informal costs) were analyzed separately. RESULTS: The average total (formal and informal) per-patient costs in the 4 settings in 1996 were $18,804. Costs increased with cognitive impairment. For patients with mild, moderate, and severe AD, annual total costs were $14,904, $19,272, and $25,860, respectively. Annual direct costs were $5520, $7044 and $10,992, respectively. CONCLUSION: Across all severity levels, we calculated a total annual cost of $8.8 billion for managed care enrollees older than 65 years in the United States. We did not estimate these costs for the population younger than 65 years because of the variability in AD prevalence estimates. Due to the increased costs for patients with more severe AD, interventions that would reverse or delay progression may result in significant cost savings.

Aged↗
PubMed1998

Combination of elevated maternal serum alpha-fetoprotein (MSAFP) and low estriol is highly predictive of anencephaly.

Increased levels of second trimester maternal serum alpha-fetoprotein (MSAFP) have long been established as a marker for neural tube defects (NTDs). In addition, decreased levels of maternal estriol in the third trimester have been reported in pregnancies with anencephalic fetuses. The purpose of this study was to evaluate whether early second trimester unconjugated serum estriol (uE3) is an independent predictor of NTDs. The study included 57,031 patients who underwent maternal serum screening with MSAFP at 14-22 weeks gestation. Of these, 23,415 also had uE3 measurements. There were 63 cases of NTD, an overall incidence of 1.1 per 1,000. Elevated MSAFP (> or =2.5 MOM) was detected in 1,346 patients, 48 of which had NTDs. Decreased uE3 (< or =0.5) was detected in 1,437 patients, 17 of which had NTDs. The incidence of NTDs was significantly higher in patients with low uE3, compared to patients with normal/high uE3 (1.15% vs. 0.09%, P < 001). Finally, 51 patients had both increased MSAFP and decreased uE3; 16 of these had NTDs, 14 of which were anencephalics. In conclusion, both elevated MSAFP and low maternal serum estriol are predictive of NTD but have a low sensitivity. The combination of abnormally elevated MSAFP and low estriol is highly predictive of NTD in particular anencephaly.

Anencephaly↗
PubMed1998

Barriers to adequate protein nutrition among hemodialysis patients.

OBJECTIVE: Determine the relative importance of potential medical, behavioral, and socioeconomic barriers to adequate protein nutrition among hemodialysis patients. DESIGN: Cross-sectional study. SETTING: All 22 chronic hemodialysis units in northeast Ohio. PATIENTS: 298 randomly selected chronic hemodialysis patients. INTERVENTION: We interviewed and abstracted the chart of each patient to assess protein nutritional status (albumin and protein catabolic rate), potential medical barriers (poor appetite, inadequate dialysis, bioincompatible dialysis membrane, difficulty chewing, and comorbid conditions), potential behavioral barriers (knowledge of protein containing foods and dietary noncompliance), and potential socioeconomic barriers (expense of protein containing foods and needing help shopping and cooking). MAIN OUTCOME MEASURE: We used logistic regression to examine the relationship between protein nutritional status and potential barriers. RESULTS: Albumin levels of <35 g/L were independently associated with Kt/V of <1.2 (odds ratio, 2.4), having more than three comorbid conditions (odds ratio, 4.0), inability to name any protein-containing foods (odds ratio, 2. 3), and needing help shopping and cooking (odds ratio, 2.6). Normalized protein catabolic rate of <1.0 g/kg/d was independently associated with poor appetite (odds ratio, 3.3), Kt/V of <1.2 (odds ratio, 3.1), and dietary compliance as indicated by low interdialytic fluid gain (odds ratio, 2.2). CONCLUSION: Three medical factors (poor appetite, inadequate dialysis, and comorbid conditions), two behavioral factors (lack of knowledge of protein containing foods and low interdialytic fluid gain), and one socioeconomic factor (needing help shopping and cooking) are independently associated with inadequate protein nutrition among hemodialysis patients. Further work is needed to develop interventions to overcome these barriers and to determine the effect of such interventions on protein nutrition and patient mortality and morbidity.

Adult↗
PubMed1998

[How to do: initial experiences with a new device in minimally invasive heart surgery].

A special surgical technique is required for minimal-invasive cardiac surgery. The view for the coronary artery anastomosis under beating heart conditions is important and coronary artery blood might prevent a clear view of the opened coronary artery vessel. A new system called VisoFlo promises to improve visualisation at the surgical site. VisoFlo delivers a column of air to help provide a clear view of anastomosis site and in addition has a controllable mist to help prevent desiccation of the graft and surrounding tissue. This system was tested on 45 patients with coronary-artery-bypass graft surgery under beating heart conditions and at 65 patients with standard coronary-artery-bypass graft surgery. Our conclusions are, that the VisoFlo system is easy to use, guarantees a clear view of the anastomosis site and the surgical work will not be impaired.

Anastomosis, Surgical↗
PubMed1997

Apoptosis of human myeloid leukemia cells induced by an inhibitor of protein phosphatases (okadaic acid) is prevented by Bcl-2 and Bcl-X(L).

Okadaic acid, an inhibitor of serine/threonine protein phosphatases 1 and 2A has been shown to cause mitotic arrest and cell death of HL-60 and K562 cells. HL-60 cells express Bcl-2 and little or no Bcl-X(L), while K562 expresses Bcl-X(L) but not Bcl-2. Since phosphorylation/dephosphorylation reactions have been suggested to be involved in the regulation of Bcl-2, we planned to investigate whether the expression of Bcl-2, Bcl-X(L) and Bax, a protein that antagonizes the antiapoptotic function of Bcl-2, are regulated in myeloid leukemia cell lines (K562, KU812 and HL-60) treated with okadaic acid. Our results indicate that exposure of all three leukemic cell lines to nanomolar concentrations of okadaic acid causes a loss of viability by activation of an apoptotic process accompanied by a marked decrease in the expression of Bcl-2, Bcl-X(L) and Bax at both mRNA and protein level, but not of c-fos, vimentin and epsilon-globin, ruling out a non-specific effect of okadaic acid. Furthermore, constitutive expression of either Bcl-X(L) or Bcl-2 by gene transfer inhibited apoptosis triggered by okadaic acid in K562 cells. Thus, we suggest that protein phosphatases may be involved in maintaining the expression of bcl-2 family genes as part of the survival machinery of the cell.

Apoptosis↗
PubMed1996

Oral alendronate induces progressive increases in bone mass of the spine, hip, and total body over 3 years in postmenopausal women with osteoporosis.

To determine the effects of long-term daily oral alendronate sodium (ALN) on bone mass in postmenopausal women with osteoporosis, 19 centers enrolled 516 postmenopausal women aged 45-80 years with spine bone mineral density (BMD) at least 2.5 SD below the mean for young premenopausal women in a 3-year, double-blind, placebo-controlled study. Subjects were randomly allocated to one of four treatment groups: placebo; alendronate, 5 or 10 mg/day for 3 years; or alendronate, 20 mg/day for 2 years followed by 5 mg/day for the 3rd year. All patients received 500 mg/day of supplemental calcium to ensure adequate calcium intake. BMD was measured by dual-energy X-ray absorptiometry at several skeletal sites. Nonsignificant mean decreases in BMD of the spine, femoral neck, and trochanter of 0.6, 0.7, and 0.4%, respectively, occurred in the placebo group at 3 years. Relative to placebo-treated patients, spine BMD increased by 5.4%, 7.4%, and 8.4% in the 5, 10, and 20/5 mg ALN groups, respectively. Increases at the femoral neck were 3.5%, 5.5%, and 4.3%, and those at the trochanter were 5.1%, 7.2%, and 7.2%, respectively. Thus, efficacy of 10 and 20/5 mg ALN was similar, whereas the 5 mg dose was less effective. BMD continued to increase over the entire 3-year study duration in the ALN-treated groups and, compared with the other dosage groups, 10 mg ALN produced the largest gains in BMD during the 3rd year. Changes in biochemical markers of bone turnover and mineral homeostasis confirmed the effect of ALN to decrease bone turnover to a new steady-state level. The safety and tolerability of ALN were comparable with those of placebo. In summary, 10 mg daily oral ALN given for 3 years significantly and progressively increases bone mass and is a generally well-tolerated treatment for osteoporosis in postmenopausal women.

Administration, Oral↗