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Biomedical subjects

Michael Miller

Publications and source records attributed to Michael Miller.

At least 19 recordsLinked to original sources
PubMed2026

Histidine Supplementation Stabilizes Hearing and Vision and Improves Growth in HARS1-Related Autosomal Recessive Disorder Associated With Usher-Like Symptoms.

Autosomal recessive HARS1-related disorder (originally described as Usher syndrome type 3B) caused by a homozygous Y454S variant in the histidyl-tRNA synthetase gene (HARS1) is characterized by progressive sensorineural hearing and vision loss and respiratory deterioration with risk for sudden death following febrile illnesses. In-vitro studies have previously shown that histidine can rescue a humanized yeast model for pathogenic HARS alleles. Fourteen children homozygous for HARS Y454S were treated with supplemental oral histidine (50 mg/kg BID) and monitored with bloodwork and physical, visual, and audiometry assessments during a 3-year clinical trial, then followed for more than 4 years on histidine in the post-trial period. Patient fibroblasts were assessed for response to histidine. Hearing and vision remained stable, and growth improved significantly. Children remained healthy, with no severe deteriorations despite exposure to bacterial and viral infections, including COVID-19. Gains in growth were maintained in the post-trial period on varying levels of histidine supplementation. Daily oral histidine supplementation in children with autosomal recessive HARS1-related disorder can ameliorate or slow the progression of disease and is safe, inexpensive, and well tolerated. This study adds to the growing list of autosomal recessive ARSopathies (aminoacyl-tRNA synthetase disorders) that are amenable to amino acid supplementation.

Humans↗
PubMed2025

Novel genetic association with migratory diapause in Australian monarch butterflies.

BACKGROUND: Monarch butterflies (Danaus plexippus) are a charismatic and culturally important North American butterfly species famous for their unique, dramatic migratory life history. While non-migratory populations of the species are widespread and apparently stable, migratory populations in North America have recently seen declines, prompting concern that the migratory phenomenon in North America may be at risk of disappearing. In contrast, a relatively recently-established monarch population in Australia has rapidly re-acquired a migratory life history following hundreds of generations of residency and successive bottlenecks as the species island-hopped across the Pacific during the late 1800s and early 1900s. The process by which migration re-emerged in Australian monarchs is not currently known. RESULTS: We raised and sequenced individuals from Queensland, Australia under environmental conditions associated with migration initiation and found strong variance in reproductive diapause, a key migratory trait, between families which was associated with variation at the spectrin beta chain protein Karst. This protein is known to be involved in diapause termination in monarchs but has not previously been identified as associated with migratory life history variance. The most strongly associated migratory SNPs are also present at a low frequency in North America, suggesting that the Australian population is leveraging standing variation which persisted across repeated bottlenecks as Monarchs spread across the Pacific. CONCLUSIONS: Our results provide an intriguing example of how the temporary loss of migration-in this case likely over hundreds of generations-may not entail the loss of genetic variation associated with this complex life history strategy.

Animals↗
PubMed2007

Baseline disease activity, hyperlipidemia, and hypertension are predictive factors for ischemic stroke and stroke severity in systemic lupus erythematosus.

BACKGROUND AND PURPOSE: To determine factors associated with ischemic stroke and stroke severity in patients with systemic lupus erythematosus. METHODS: Between 1992 and January 2005, 238 consecutive systemic lupus erythematosus patients with no history of stroke were followed-up longitudinally at the Maryland Lupus Clinic. Patients were monitored quarterly for a mean of 8 years after their systemic lupus erythematosus diagnosis, and 44 patients (19%) developed first-ever ischemic stroke. At the end of study, Cox proportional regression analyses were used to determine the effect of baseline clinical variables of systemic lupus erythematosus patients in relation to the subsequent occurrence of ischemic stroke and stroke severity after first-ever ischemic strokes. Severe stroke was defined as having a National Institute of Health Stroke Scale > or =6. RESULTS: Severe ischemic strokes occurred in 34 of 44 (77%) patients. Baseline predictors of ischemic strokes and severe ischemic strokes included disease activity, hyperlipidemia, and hypertension. CONCLUSIONS: Severe ischemic strokes in systemic lupus erythematosus are not uncommon. Aggressive primary and secondary stroke prevention measures, particularly treatment of hyperlipidemia and hypertension, as well as vigorous treatment of clinical symptoms of active lupus, are needed to prevent serious morbidity and neurological disability.

Adult↗
PubMed2007

Efficacy and safety of tenofovir double-dose in treatment-experienced HIV-infected patients: the TENOPLUS study.

Drug resistance is an increasing problem in the treatment of HIV infection. Tenofovir has been shown to inhibit HIV replication even with thymidine-associated resistance mutations (TAMs) if they are limited to two or less. Double-dose of tenofovir disoproxil fumarate (TDF) (600 mg QD) was used to determine weather the drug could be virologically effective in patients harbouring HIV-strains resistant to nucleoside analogues (NRTI). A pilot, open, non-comparative add-on study, where patients failing a current antiretroviral regimen, with at least two TAMs, and naive for tenofovir, were given tenofovir 600 mg once-daily for 4 weeks, in addition to their current failing antiretroviral regimen. The primary end-point was the percentage of patients with plasma viral load (VL) reduction of at least 0.8 log(10) between baseline and week 4 (W4). Ten patients were enrolled. At baseline, the median viral load was 3.66 log(10) copies/ml (range 3.13-4.03) and the median CD4 cell count was 407/mm(3) (range 136-1102). The percentage of patients with reduction the viral load > or =0.8 log(10) was 40% at W4. After 4 weeks of treatment with tenofovir 600 mg, the median decrease in the viral load was -0.61 log(10) (range -0.05; -0.88) and the median gain of CD4 was +109/mm(3). Despite a twofold increase tenofovir plasma concentrations, no serious drug-related adverse event were recorded except for one patient experiencing an de Fanconi syndrome at week 2. This add-on pilot study supports the concept of double dose tenofovir to virologically overcome the decreased sensitivity of NRTI-resistant viruses. However, the safety of this regimen needs to be considered carefully.

Adenine↗
PubMed2007

Optimal treatment of dyslipidemia in high-risk patients: intensive statin treatment or combination therapy?

A recent update to the National Cholesterol Education Program's Adult Treatment Panel III guidelines suggests low-density lipoprotein cholesterol (LDL-C) goals of <70 mg/dL in very-high-risk patients and <100 mg/dL in high-risk patients. Currently available 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) are not equal in their ability to lower LDL-C, and it is unlikely that the substantial LDL-C reductions that are often needed in high-risk persons can be achieved with starting doses of some of the older statins. Possible alternatives in such cases include the use of high-dose statin therapy, a more efficacious statin, or combination therapy. Recent clinical data have demonstrated a greater likelihood of coronary heart disease event reduction with aggressive statin therapy that lowers LDL-C in a robust fashion (>30%-40%) than with moderate therapy. Until data from ongoing trials of combination therapy are available, however, monotherapy with a potent statin should be initiated to lower LDL-C. Nonetheless, for residual elevation in triglycerides and/or reduced high-density lipoprotein cholesterol, adding a second agent (eg, fenofibrate, niacin) is a reasonable option.

Algorithms↗
PubMed2006

Role of LCAT in HDL remodeling: investigation of LCAT deficiency states.

To better understand the role of LCAT in HDL metabolism, we compared HDL subpopulations in subjects with homozygous (n = 11) and heterozygous (n = 11) LCAT deficiency with controls (n = 22). Distribution and concentrations of apolipoprotein A-I (apoA-I)-, apoA-II-, apoA-IV-, apoC-I-, apoC-III-, and apoE-containing HDL subpopulations were assessed. Compared with controls, homozygotes and heterozygotes had lower LCAT masses (-77% and -13%), and LCAT activities (-99% and -39%), respectively. In homozygotes, the majority of apoA-I was found in small, disc-shaped, poorly lipidated prebeta-1 and alpha-4 HDL particles, and some apoA-I was found in larger, lipid-poor, discoidal HDL particles with alpha-mobility. No apoC-I-containing HDL was noted, and all apoA-II and apoC-III was detected in lipid-poor, prebeta-mobility particles. ApoE-containing particles were more disperse than normal. ApoA-IV-containing particles were normal. Heterozygotes had profiles similar to controls, except that apoC-III was found only in small HDL with prebeta-mobility. Our data are consistent with the concepts that LCAT activity: 1) is essential for developing large, spherical, apoA-I-containing HDL and for the formation of normal-sized apoC-I and apoC-III HDL; and 2) has little affect on the conversion of prebeta-1 into alpha-4 HDL, only slight effects on apoE HDL, and no effect on apoA-IV HDL particles.

Analysis of Variance↗
PubMed2006

A simple spreadsheet-based, MIAME-supportive format for microarray data: MAGE-TAB.

BACKGROUND: Sharing of microarray data within the research community has been greatly facilitated by the development of the disclosure and communication standards MIAME and MAGE-ML by the MGED Society. However, the complexity of the MAGE-ML format has made its use impractical for laboratories lacking dedicated bioinformatics support. RESULTS: We propose a simple tab-delimited, spreadsheet-based format, MAGE-TAB, which will become a part of the MAGE microarray data standard and can be used for annotating and communicating microarray data in a MIAME compliant fashion. CONCLUSION: MAGE-TAB will enable laboratories without bioinformatics experience or support to manage, exchange and submit well-annotated microarray data in a standard format using a spreadsheet. The MAGE-TAB format is self-contained, and does not require an understanding of MAGE-ML or XML.

Computational Biology↗
PubMed2006

Impact of lowering triglycerides on raising HDL-C in hypertriglyceridemic and non-hypertriglyceridemic subjects.

Although an inverse association between triglyceride (TG) and (HDL-C) is well documented, the impact of lowering TG on HDL-C levels has not been well established. Therefore, data were analyzed in 151 consecutive dyslipidemic patients who made multiple visits (n=1830) to the University of Maryland Preventive Cardiology Center between 1991 and 2005. At baseline, fasting TG levels at or above the median (178 mg/dL) were associated with significantly lower HDL-C than TG levels below the median (32.6+/-11.1 mg/dL versus 45.1+/-14.2 mg/dL; P<0.0001). Following baseline evaluation, various therapies were employed (i.e., dietary, exercise, medication) to reduce mean LDL (147.3+/-53.4 mg/dL) and TG (306.1+/-414.9 mg/dL). Using a fully adjusted mixed regression model, each 50 mg/dL reduction in TG was independently associated with a 0.5 mg/dL increase in HDL-C in hypertriglyceridemic subjects (e.g., TG> or =200 mg/dL) and a 1.7 mg/dL increase in HDL-C in the absence of elevated TG (P<0.0001). The use of niacin (P<0.0001), statins (P=0.0003) and fibrates (P=0.03) were also associated with significant increases in HDL-C beyond that anticipated with TG reduction. These data indicate that lowering TG is independently and inversely correlated with HDL-C, effects that are most pronounced in the absence of hypertriglyceridemia.

Alcohol Drinking↗
PubMed2006

Do mutations causing low HDL-C promote increased carotid intima-media thickness?

BACKGROUND: Although observational data support an inverse relationship between high-density lipoprotein (HDL) cholesterol and coronary heart disease (CHD), genetic HDL deficiency states often do not correlate with premature CHD. METHODS: Carotid intima-media thickness (cIMT) measurements were obtained in cases comprising 10 different mutations in LCAT, ABCA1 and APOA1 to further evaluate the relationship between low HDL resulting from genetic variation and early atherosclerosis. RESULTS: In a 1:2 case-control study of sex and age-related (+/-5 y) subjects (n=114), cIMT was nearly identical between cases (0.66+/-0.17 cm) and controls (0.65+/-0.18 cm) despite significantly lower HDL cholesterol (0.67 vs. 1.58 mmol/l) and apolipoprotein A-I levels (96.7 vs. 151.4 mg/dl) (P<0.05) CONCLUSIONS: Genetic variants identified in the present study may be insufficient to promote early carotid atherosclerosis.

Cholesterol, HDL↗
PubMed2006

[Angiosarcoma of the liver as a rare cause of rapidly progressive liver failure].

BACKGROUND: Angiosarcoma of the liver is a rare, highly malignant and sometimes diffusely infiltrating vessel tumor with rapid progression and poor prognosis. CASE REPORT: A 46-year-old male patient with rapidly progressive liver failure, initially regarded as decompensation of known alcoholic liver cirrhosis, is reported. The patient was referred to the authors' center for evaluation of liver transplantation, but a massive weight loss despite long absence of any alcohol intake raised the suspicion of a malignant disease. The abdominal ultrasound examination showed a massive hepatomegaly with an extremely inhomogeneous echo structure as well as moderate ascites. A following MRI demonstrated diffuse focal contrast enhancement in the entire liver parenchyma, confirming diffuse infiltration of the organ by a malignant tumor. In addition, MRI was suspicious of bone metastases. The usual tumor markers were normal. Sonographically guided percutaneous liver biopsy established the diagnosis of a malignant vascular tumor with diffuse infiltration of the liver parenchyma. 3 days later the patient died of uncontrollable bleeding from esophageal varices. Macroscopic examination of the liver during autopsy showed multiple lacunae filled with blood. Therefore, the differential diagnosis of a peliosis hepatis was raised. However, histology confirmed the diagnosis of a malignant angiosarcoma with diffuse osseous metastases. CONCLUSION: A diffuse infiltration of the liver by an angiosarcoma in the absence of any definite lesions may lead to a substantial delay of the diagnosis. The only relevant differential diagnosis in this case is the equally rare peliosis hepatis.

Biopsy↗
PubMed2006

The two novel CETP mutations Gln87X and Gln165X in a compound heterozygous state are associated with marked hyperalphalipoproteinemia and absence of significant coronary artery disease.

High levels of high-density lipoprotein cholesterol (HDL-C) occur with cholesteryl ester transfer protein (CETP) deficiency. However, the extent to which CETP deficiency states may be associated with protection against coronary artery disease (CAD) has been controversial. We evaluated a Greek pedigree with high levels of HDL-C and no history of premature CAD. The proband, a 45-year-old male with an HDL-C of 194 mg/dl with absent CETP activity, was heterozygous for two novel CETP mutations (Q87X and Q165X). A 64-slice multidetector CT scan revealed minimal (<10%) narrowing of the proximal left anterior descending artery without any other evidence of coronary atherosclerosis. In contrast to previous studies, these data suggest that complete CETP deficiency does not promote premature atherosclerosis. However, it remains unclear as to whether the relative lack of coronary atherosclerosis was the direct consequence of CETP deficiency and/or the lack of traditional CAD risk factors.

Adolescent↗
PubMed2006

A physico-chemical survey of inland lakes and saline ponds: Christmas Island (Kiritimati) and Washington (Teraina) Islands, Republic of Kiribati.

The equatorial Pacific Ocean atoll islands of Kiritimati and Teraina encompass great physical, chemical and biological variability within extreme lacustrine environments. Surveys of lake chemistry and sediments revealed both intra- and inter-island variability. A survey of more than 100 lakes on Kiritimati found salinities from nearly fresh to 150 ppt with the highest values occurring within the isolated, inland portions of the island away from the influence of groundwater or extreme tides. Dissolved oxygen (DO) and pH values also showed considerable variability with a less regular spatial pattern, but were both generally inversely related to salinity. Series of lakes, progressively more isolated from marine communication, present a modern analog to the chemical and morphologic evolution of presently isolated basins. Sediments on both islands consist of interbedded red and green silt, possibly degraded bacterial mat, overlying white, mineralogenic silt precipitate. Variability may be indicative of shifts in climatological parameters such as the El Niño Southern Oscillation (ENSO) or the Pacific Intertropical Convergence Zone (ITCZ).

Journal Article↗
PubMed2006

Effect of statins on platelet PAR-1 thrombin receptor in patients with the metabolic syndrome (from the PAR-1 inhibition by statins [PARIS] study).

We investigated whether, in primary prevention patients with metabolic syndrome, statins affect the platelet protease-activated receptor-1 (PAR-1) thrombin receptor by performing serial measurements of its activity and the antigen expression level by flow cytometry before and during treatment. Recent data from randomized trials of statins are compatible with the possibility of clinically relevant pleiotropic effects. The use of statins is associated with a reduced thrombosis burden and diminished platelet activity, as shown in animal models and in vitro studies. Seventy patients with the metabolic syndrome who were not taking antiplatelet agents were assigned consecutively at starting doses at the discretion of the responsible clinician to 1 of 6 statins (atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, or simvastatin) or to a no-statin group for 6 weeks. Platelet expression of intact (SPAN12 antibody) and cleaved (WEDE15) PAR-1 thrombin receptors were assessed by flow cytometry at baseline and at weeks 4 and 6 of treatment. At baseline, no difference was found in receptor expression. However, after 4 weeks of treatment, all statins had significantly inhibited (46% to 55%) the activated epitope of PAR-1 expression. After 6 weeks, inhibition remained, despite a slight rebound (22% to 37%). Also, a delayed pattern of inhibition of the intact PAR-1 receptor epitope was found. In conclusion, all statins inhibited the activity and antigen level of the platelet PAR-1 thrombin receptor, which has a major role in regulating platelet activity and thrombin formation. These observational data offer a plausible mechanism for the recently demonstrated pleiotropic effects of statins that may contribute to early clinical benefit.

Blood Platelets↗
PubMed2006

A physiologic imaging pilot study of breast cancer treated with AZD2171.

BACKGROUND: This pilot study combined physiologic imaging, microcomputed tomography, and histologic tumor evaluation with a xenograft model of breast cancer to identify surrogates likely to correlate with response to AZD2171, an inhibitor of the vascular endothelial growth factor (VEGF) receptor tyrosine kinases. EXPERIMENTAL DESIGN: MCF-7 cells transfected with vector (MCF-7neo) or VEGF (MCF(VEGF)) were implanted in the right and left mammary fat pads of 75 athymic mice. Treatment with AZD2171 (5 mg/kg/d) or vehicle control was initiated once tumors were established. Positron emission tomography with [11C]carbon monoxide to measure blood volume, [18F]fluoromethane to measure perfusion, and [18F]fluorodeoxyglucose to measure glucose utilization was done at baseline, and after 24 hours, 72 hours, and 4 weeks of treatment. After imaging, tumors were analyzed for microvessel density, proliferation, and VEGF expression. RESULTS: AZD2171 induced significant inhibition of tumor growth in established MCF-7(neo) xenografts and regression of established MCF-7(VEGF) xenografts. An acute decrease in blood flow was detected in MCF-7(VEGF) tumors at 24 hours (P = 0.05). Tumor blood volume was increased in the MCF-7(VEGF) tumors but correlated with tumor size; blood volume did not change with AZD2171 therapy. Glucose utilization correlated with tumor size and did not change with acute or chronic AZD2171 therapy. Unlike blood flow and blood volume, glucose utilization was similar in MCF-7neo and MCF-7(VEGF) tumors. Microvessel density and proliferation acutely decreased in MCF-7(VEGF) tumors but returned to baseline during chronic therapy. CONCLUSIONS: [18F]Fluoromethane imaging may be a useful surrogate for biological activity of AZD2171 with changes identified within 24 hours of starting therapy.

Angiogenesis Inhibitors↗
PubMed2006

Infection surveillance and control programs in the Department of Veterans Affairs nursing home care units: a preliminary assessment.

A survey was conducted to assess the capacity and current practices of the infection surveillance and control programs at the Department of Veterans Affairs' 130 nursing home care units (VA NHCUs) covering a total of 15,006 beds in 2003. All 130 VA NHCUs responded to the survey, although not all NHCUs answered every question. The majority of the VA NHCUs provided specialized services that might pose increased risks of infection. For every 8 to 10 VA NHCU beds, there was 1 regular-pressure or negative-pressure infection control room available. Each VA NHCU had an active ongoing infection surveillance and control program managed by highly educated infection control personnel (ICP), of which 96% had a minimum of a bachelor degree. A median of 12 hours per week of these ICP efforts was devoted to the infection surveillance and control activities. The most frequently used surveillance methods were targeted surveillance for specific infections and for specific organisms. Most VA NHCUs conducted surveillance for antibiotic-resistant organisms. However, VA NHCUs did not use a uniform set of definitions for nosocomial infections for their infection surveillance and control purposes. We conclude that VA NHCUs have a considerable infrastructure and capacity for infection surveillance and control. This information can be used to develop a nationwide VA NHCU nosocomial infection surveillance system.

Health Care Surveys↗
PubMed2006

FuGE: Functional Genomics Experiment Object Model.

This is an interim report on the Functional Genomics Experiment (FuGE) Object Model. FuGE is a framework for creating data standards for high-throughput biological experiments, developed by a consortium of researchers from academia and industry. FuGE supports rich annotation of samples, protocols, instruments, and software, as well as providing extension points for technology specific details. It has been adopted by microarray and proteomics standards bodies as a basis for forthcoming standards. It is hoped that standards developers for other omics techniques will join this collaborative effort; widespread adoption will allow uniform annotation of common parts of functional genomics workflows, reduce standard development and learning times through the sharing of consistent practice, and ease the construction of software for accessing and integrating functional genomics data.

Computer Simulation↗