Intensive versus moderate lipid lowering with statins after acute coronary syndromes.
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Angina, Unstable↗
Biomedical subjects
Michael Miller
Publications and source records attributed to Michael Miller.
Ethyl glucuronide: a biomarker to identify alcohol use by health professionals recovering from substance use disorders.
AIMS: Physicians recovering from substance-related disorders are usually allowed to return to practice if they agree to remain abstinent from drugs, including alcohol, and to undergo random urine testing. Over 9000 physicians are currently involved in such monitoring programs in the US. To date, it has been difficult to adequately monitor abstinence from alcohol due to the short half-life of alcohol and no other highly specific marker. Ethyl glucuronide (EtG), a direct metabolite of alcohol, offers an extended window for assessment of drinking status (up to 5 days). Our aim was to assess the potential value of EtG testing in abstinence-based monitoring programs. PATIENTS AND METHODS: Urine samples were obtained from 100 participants in a physician monitoring program and additional samples were subsequently obtained 'for cause', 'to verify positive urine alcohol, when drinking was denied' and 'in high risk individuals'. All participants had signed contracts agreeing to remain abstinent from mood-altering drugs, including alcohol, and had agreed to random urine testing. EtG was determined using LC/MS-MS in addition to standard testing. The main outcome measure were urine specimens positive for EtG versus those positive based on standard testing for alcohol and other drugs. RESULTS: Among the initial 100 random samples collected, no sample was positive for alcohol using standard testing; however, seven were positive for EtG (0.5-196 mg/l), suggesting recent alcohol use. Subsequent EtG testing was performed clinically during the course of monitoring. Of the 18 tests performed to date, eight of eight tests performed 'for cause' were positive for EtG but negative for all other drugs including urine alcohol. All eight were confirmed positive by self reported drinking by the patient when confronted regarding the positive test result. Of six tests performed to 'confirm a positive urine alcohol' two were positive for EtG and confirmed positive by self reported drinking. For the other four samples, especially as two are from a diabetic, in vitro fermentation of ethanol is discussed. CONCLUSIONS: These data suggest that physicians in monitoring programs have a higher rate of unrecognized alcohol use than previously reported. Incorporation of EtG testing into alcohol abstinence monitoring can strengthen these programs.
Biomarkers↗
Acetabular revision with a modular anti-protrusio acetabular component.
Current anti-protrusio cages are non-porous-coated and 1 piece and they require liner cementation. These factors limit bone ingrowth, trials, and modularity. Results of a completely modular porous-coated anti-protrusio component (MAPC) are presented. Sixty-three acetabular revisions with MAPC were performed from 1998-2001 by 2 surgeons. Average follow-up was 29 months (range, 24-50). 30/63 (48%) had Paprosky type 3A or B defects. 55/63 (87%) MAPCs remain in place. Four components were removed for infection, 3 for loosening, and 1 for malposition. Eight hips dislocated, requiring 6 reoperations. Two MAPCs are radiographically loose but asymptomatic. At short-term follow-up, these results are comparable to conventional 1-piece anti-protrusio cages. Advantages include the potential for bone ingrowth and long-term fixation, surgical technique similar to large hemispherical components, ability to trial, and modularity.
Acetabulum↗
Analysis of the HIV-1 gp41 specific immune response using a multiplexed antibody detection assay.
A fluorescence-based, multiplexed, antibody-binding and mapping assay was developed to characterize antibody responses in HIV-1-infected individuals to the ectodomain of the HIV-1 gp41 envelope glycoprotein. The antigen panel included intact recombinant gp41, the fusion peptide region, the polar region, the N-heptad region, the C-heptad region as well as overlapping epitopes in the 2F5 and 4E10 monoclonal antibody-binding regions. The panel included both native and constrained peptides specifically designed to mimic putative gp41 prefusion and fusion intermediates. The results of these analyses revealed a broad pattern of immune responses against the test antigens, suggesting that none of these gp41 regions are immunologically silent. The HIV-1-positive sera were also evaluated using infectivity inhibition assays. No correlation was evident between the breadth or magnitude of specific anti-gp41 reactivities and virus neutralization potency. These evaluations demonstrated the substantial potential of the multiplexed antibody binding and mapping assay for rapid and sensitive analysis of complex antibody responses.
Amino Acid Sequence↗
Shielding of the contralateral breast during tangential irradiation.
The purpose of this study was to investigate both optimal and practical contralateral breast shielding during tangential irradiation in young patients. A shaped sheet of variable thickness of lead was tested on a phantom with rubber breasts, and an optimized shield was created. Testing on 18 consecutive patients 50 years or younger showed shielding consistently reduced contralateral breast dose to at least half, with small additional reduction after removal of the medial wedge. For younger patients in whom radiation exposure is of considerable concern, a simple shield of 2 mm lead thickness proved practical and effective.
Adult↗
Genetic determinants of low high-density lipoprotein cholesterol.
PURPOSE OF REVIEW: High-density lipoprotein cholesterol (HDL-C) has been well established as an inverse predictor of coronary heart disease (CHD), and in recent years, investigations have focused on the genetic regulation of high-density lipoprotein. Although numerous candidate genes contribute to the low HDL-C phenotype, their impact on CHD is heterogeneous, reflecting diverse gene-gene interactions and gene-environmental relationships. This review summarizes recent data involving HDL regulatory genes and their role in atherothrombosis. RECENT FINDINGS: The primary genetic determinants associated with relative HDL-C deficiency states are the ATP binding cassette protein, ABCA1; apolipoprotein (APO) A1; and lecithin cholesteryl acyl transferase. Other potentially important candidates invoked in low HDL-C syndromes in humans include APOC3, lipoprotein lipase, sphingomyelin phosphodiesterase 1, and glucocerebrosidase. Molecular variation in ABCAI and APOAI and, in selected cases, lecithin cholesteryl acyl transferase deficiency have been associated with increased CHD, whereas two notable variants, APOAIMilano and APOAIParis, are associated with reduced risk. SUMMARY: Low HDL-C syndromes have generally been correlated with an increased risk of CHD. However, single-gene abnormalities responsible for HDL-C deficiency states may have variable effects on atherothrombotic risk.
ATP Binding Cassette Transporter 1↗
Composite resin fluorescence.
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Acrylic Resins↗
Effectiveness of simvastatin therapy in raising HDL-C in patients with type 2 diabetes and low HDL-C.
OBJECTIVE: To evaluate the efficacy of high and moderate doses of simvastatin (80 and 40 mg), for raising high density lipoprotein-cholesterol (HDL-C), improving HDL sub-fractions, and affecting other parameters, including high sensitivity C-reactive protein (hs-CRP), in patients with type 2 diabetes mellitus (DM) and low HDL-C. RESEARCH DESIGN AND METHODS: This double-blind, placebo-controlled, randomized, 3-period, complete block, 6-week crossover study examined the efficacy of simvastatin in adult men and women (N = 151) with stable type 2 DM (HbA(1C) < 9%), low density lipoprotein-cholesterol (LDL-C) > 100 mg/dL (2.6 mmol/L), HDL-C < 40 mg/dL (< 1 mmol/L), and fasting triglyceride level > 150 (> 1.7 mmol/L) and < 700 mg/dL (< 7.9 mmol/L). This study included adult men (71%) and women (29%) of various races (89% white, 6% black, 1% Asian, 3% other) enrolled from 29 practice-based sites in the United States. MAIN OUTCOME MEASURES: Percentage change in HDL-C from baseline at the end of each 6-week treatment interval. RESULTS: Both simvastatin 80 and 40 mg significantly increased total HDL-C from baseline (mean increases of 8% +/- 1 [SE] and 5% +/- 1, respectively; p < 0.001) compared with placebo, and significantly reduced plasma concentrations of LDL-C (p < 0.001), triglycerides (p < 0.001), apolipoprotein B (p < 0.001), and hs-CRP (p < or = 0.012). Compared with simvastatin 40 mg, the 80 mg dose provided additional efficacy. Simvastatin 80 mg also significantly (p < 0.001) increased HDL(2) from baseline (14% +/- 3[SE]) and placebo phases (10 +/- 3). An exploratory analysis showed 87% (simvastatin 80 mg) and 82% (simvastatin 40 mg) of patients reached the NCEP ATP III treatment goals for LDL-C compared with 14% on placebo. CONCLUSIONS: Both simvastatin 80 and 40 mg raise HDL-C and improve other measures associated with elevated coronary risk in patients with type 2 DM and low HDL-C.
Adult↗
Treatment of trigeminal neuralgia with linear accelerator radiosurgery: initial results.
OBJECT: Radiosurgery has emerged as an important treatment of trigeminal neuralgia. Substantial advantages have been demonstrated in safety and comfort over other modalities. Radiosurgical treatment of trigeminal neuralgia has been well investigated with gamma knife devices involving fixed cobalt sources. Few reports exist concerning trigeminal neuralgia treated using linear accelerator (LINAC)-based devices. In recent years these devices have reached the level of mechanical precision that is required for such functional treatments. The authors describe their initial experience with radiosurgical treatment of trigeminal neuralgia when using a BrainLAB Novalis LINAC device equipped with the commercially available 4-mm collimator. METHODS: A total of 32 patients were treated in a 12-month period between November 2002 and November 2003. The median patient age was 67 years (range 38-84 years). Facial pain was graded using the Barrow Neurological Institute (BNI) scoring system. All patients' pain was BNI Grade IV or V prior to treatment. Of these patients, 22 were undergoing initial treatment, and 10 were undergoing retreatment for recurrent pain following various treatments including percutaneous procedures, gamma knife surgery (GKS), or microvascular decompression. Two patients had multiple sclerosis. In patients undergoing initial radiosurgery, the most proximal segment of the cisternal portion of the trigeminal nerve received 85 to 90 Gy administered in a 5- or 7-noncoplanar arc single-isocenter plan with a 4-mm circular collimator. In patients undergoing repeated radiosurgery, the target received 60 Gy. Overall good and excellent results (BNI Grade I, II, or III) were achieved in 25 (78%) of 32 patients. The median time to pain relief was 6 weeks. Fair results (improvement in pain with BNI Grade IV) were achieved in three patients (9%), and poor results (no improvement in pain and BNI Grade IV or V) were seen in four (13%). Two patients demonstrated new trigeminal dysfunction following treatment. No other complications occurred. CONCLUSIONS: High-precision imaging and LINAC instrumentation have allowed for treatment of trigeminal neuralgia with results and safety comparable to those achieved using GKS. Linear accelerator-based radiosurgery with the Novalis device is a safe and effective method of managing trigeminal neuralgia and may become the preferred means at centers where the technology is available.
Adult↗
Genotypic determinants of the virological response to tenofovir disoproxil fumarate in nucleoside reverse transcriptase inhibitor-experienced patients.
OBJECTIVE: To assess the genotypic determinants of the virological response to tenofovir disoproxil fumarate (TDF) in a multicentre cohort of antiretroviral (ARV)-experienced patients receiving TDF as a part of a salvage therapy. METHODS: HIV-1 genotype was assessed at baseline in a subgroup of 161 patients of the French expanded access program receiving a stable TDF-including regimen for 3 months or more. Reverse transcriptase mutations associated with the viral load decrease at month 3 with a P-value <0.15 were retained for the construction of a mutation score. The score was then validated using a multivariate analysis and bootstrap resampling method. RESULTS: The strongest association with decrease in viral load was observed with a set of seven mutations (TDF mutation score) that consisted of M41L, E44D, D67N, T69D/N/S, L74V, L210W and T215Y/F RT mutations. The RT K65R mutation and the insertions at codon 69 were not included in the analysis due to low prevalences. A TDF mutation score of < or = 2 predicted the absence of resistance to TDF and > or = 6 mutations predicted resistance to TDF with corresponding reductions in viral load of -1.3 +/- 1.1, and +0.1 +/- 0.7 log10 copies/ml, respectively. In patients with a TDF mutation score of 3-5, the decrease in viral load was -0.8 +/- 1.0 log10 copies/ml and was considered possibly resistant. In the multivariate analysis, a TDF mutation score > or = 6, previous use of amprenavir, indinavir and lopinavir, and co-prescription of didanosine were associated with a worse virological response. The bootstrap analysis showed the robustness of the TDF mutation score. CONCLUSION: In ARV-experienced patients receiving TDF-containing regimens, a score derived from seven reverse transcriptase mutations was shown to be independently predictive of the virological response.
Adenine↗
Clinically validated genotype analysis: guiding principles and statistical concerns.
Whereas previously the output of HIV resistance tests has been based on therapeutically arbitrary criteria, there is now an ongoing move towards correlating test interpretation with virological outcomes on treatment. This approach is undeniably superior, in principle, for tests intended to guide drug choices. However the predictive accuracy of a given stratagem that links genotype or phenotype to drug response is strongly influenced by the study design, data capture and analytical methodology used to derive it. For genotyping, the most widely used resistance tool in clinical practice, these considerations are further complicated by the range of mutational patterns present in the treated population. There is no definitively superior methodology for generating a genotype-response association for use in interpreting a resistance test, and the various approaches used to date all have their strengths and weaknesses. This review discusses the processes involved in constructing such tools, with particular emphasis on establishing validated mutation score rules, and examines the key issues and confounding factors that influence predictive accuracy outside the originating dataset. Since the size of the sample is a key influence on the statistical power to determine an effect, it is hoped that a greater understanding of the influence of study design and methodology will assist the development of standardized outcome measures and reporting formats that allow data pooling at the international level.
Anti-HIV Agents↗
Single-step, self-etch adhesives behave as permeable membranes after polymerization. Part I. Bond strength and morphologic evidence.
PURPOSE: To test the hypotheses that microtensile bond strengths of single-step, self-etch adhesives to hydrated dentin are adversely affected by delayed-activation of a light-cured composite, as well as the use of a chemical-cured composite. METHODS: Seven commercially available and one experimental single-step, self-etch adhesives were bonded to hydrated human dentin. A dual-cured composite was used and activated using: [1] the light-cured mode (base paste only-control), [2] the chemical-cured mode (base and catalyst pastes, in the dark); and [3] delayed light-activation (base syringe only, left on top of cured adhesives in the dark for 20 minutes before activation). After microtensile bond strength evaluation, fractured samples were examined using SEM. Intact, unstressed interfaces of [1] and [3] were examined with TEM. Microtensile bond strengths were also evaluated for selected adhesives bonded to dehydrated dentin and coupled with the composite activated by [2] or [3]. RESULTS: For all adhesives, bond strengths decreased significantly to bonded hydrated dentin when the composites were activated with [2] or [3] (P< 0.001). Whereas the hybrid layer-adhesive interface was intact, water-blisters that developed along the adhesive-composite interface in these two modes were responsible for the decline in bond strength. When bonded to dehydrated dentin, delayed light-activation of the light-cured composite did not result in compromised bond strength. The results of chemical-cured composites improved but were more variable and system-dependent.
Composite Resins↗
Primary MALT lymphoma of the dura in a patient with active scleroderma.
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Brain Neoplasms↗
Major malformations in offspring of women with epilepsy.
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Abnormalities, Drug-Induced↗
Pharmacodynamics of the type II calcimimetic compound cinacalcet HCl.
Calcimimetic compounds, which activate the parathyroid cell Ca(2+) receptor (CaR) and inhibit parathyroid hormone (PTH) secretion, are under experimental study as a treatment for hyperparathyroidism. This report describes the salient pharmacodynamic properties, using several test systems, of a new calcimimetic compound, cinacalcet HCl. Cinacalcet HCl increased the concentration of cytoplasmic Ca(2+) ([Ca(2+)](i)) in human embryonic kidney 293 cells expressing the human parathyroid CaR. Cinacalcet HCl (EC(50) = 51 nM) in the presence of 0.5 mM extracellular Ca(2+) elicited increases in [Ca(2+)](i) in a dose- and calcium-dependent manner. Similarly, in the presence of 0.5 mM extracellular Ca(2+), cinacalcet HCl (IC(50) = 28 nM) produced a concentration-dependent decrease in PTH secretion from cultured bovine parathyroid cells. Using rat medullary thyroid carcinoma 6-23 cells expressing the CaR, cinacalcet HCl (EC(50) = 34 nM) produced a concentration-dependent increase in calcitonin secretion. In vivo studies in rats demonstrated cinacalcet HCl is orally bioavailable and displays approximately linear pharmacokinetics over the dose range of 1 to 36 mg/kg. Furthermore, this compound suppressed serum PTH and blood-ionized Ca(2+) levels and increased serum calcitonin levels in a dose-dependent manner. Cinacalcet was about 30-fold more potent at lowering serum levels of PTH than it was at increasing serum calcitonin levels. The S-enantiomer of cinacalcet (S-AMG 073) was at least 75-fold less active in these assay systems. The present findings provide compelling evidence that cinacalcet HCl is a potent and stereoselective activator of the parathyroid CaR and, as such, might be beneficial in the treatment of hyperparathyroidism.
Animals↗
Novel polypyrimidine variation (IVS46: del T -39...-46) in ABCA1 causes exon skipping and contributes to HDL cholesterol deficiency in a family with premature coronary disease.
Recent studies have implicated mutations in the ATP-binding cassette transporter A1, ABCA1, as a cause of Tangier disease (TD) and familial hypoalphalipoproteinemia (FHA). We investigated a proband with very low levels of high-density lipoprotein cholesterol (HDL-C, 6 mg/dL) and a history of premature coronary heart disease (CHD). Sequencing of the ABCA1 gene revealed 2 distinct variants. The first mutation was a G5947A substitution (R1851Q). The second mutation was a single-nucleotide deletion of thymidine in a polypyrimidine tract located 33 to 46 bps upstream to the start of exon 47. This mutation does not involve the 3' acceptor splice site and is outside the lariat branchpoint sequence (IVS46: del T -39...-46). Amplification of cDNA obtained in cultured fibroblasts of the proband and affected family member revealed an abnormally spliced cDNA sequence with skipping of exon 47. These variants were not identified in over 400 chromosomes of healthy whites. Compound heterozygotes (n=4) exhibited the lowest HDL-C (11+/-5 mg/dL) and ApoA-I (35+/-15 mg/dL) compared with wild-type (n=25) (HDL-C 51+/-14 mg/dL; ApoA-I 133+/-21 mg/dL) (P<0.0005) or subjects affected with either R1851Q (n=6) (HDL-C 36+/-8; ApoA-I 117+/-19) or IVS46: del T -39...-46 (n=5) (HDL-C 31+9; ApoA-I 115+28 (P<0.01). These data suggest that polypyrimidine tract variation may represent a novel mechanism for altered splicing and exon skipping that is independent of traditional intronic variants as previously identified in acceptor/donor splice regions or the lariat branchpoint domain.
ATP Binding Cassette Transporter 1↗
Estimating the client costs of addiction treatment: first findings from the client drug abuse treatment cost analysis program (Client DATCAP).
The costs of addiction treatment services are an important determinant of the cost-effectiveness of a program, and therefore, of relevance to addiction treatment providers, insurance companies and, patients. Several methods have been developed to estimate the costs of substance abuse treatment services. One such method is the drug abuse treatment cost analysis program (DATCAP), which collects resource use and cost data from the treatment program perspective and has been used in numerous published economic evaluation studies. However, no single widely-used, standardized instrument is currently available to estimate costs specifically incurred by clients in treatment. In response to that need, this article introduces the Client DATCAP and presents process, survey-specific, and quantitative findings from a Pilot Study to estimate the client costs of attending outpatient and inpatient treatment. The preliminary findings suggest that the self-administered Client DATCAP is a feasible and practical instrument for estimating costs incurred by clients in treatment, with completion time amounting to less than 10 min. Furthermore, client costs had a considerable range across respondents, with time costs consistently accounting for the largest cost component. Findings from the Pilot Study led to the development and release of edition 2 of the outpatient and inpatient modules of the Client DATCAP.
Adult↗
CCR5 antagonists: 3-(pyrrolidin-1-yl)propionic acid analogues with potent anti-HIV activity.
[reaction: see text] A novel approach to alpha,alpha-disubstituted-beta-amino acids (beta(2,2)-amino acids) was employed in the synthesis of a series of 3-(pyrrolidin-1-yl)propionic acids possessing high affinity for the CCR5 receptor and potent anti-HIV activity. The rat pharmacokinetics for these new analogues featured higher bioavailabilities and lower rates of clearance as compared to cyclopentane 1.
Anti-HIV Agents↗