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Biomedical subjects

J J McCarthy

Publications and source records attributed to J J McCarthy.

At least 19 recordsLinked to original sources
PubMed2006

Recent Greenland ice mass loss by drainage system from satellite gravity observations.

Mass changes of the Greenland Ice Sheet resolved by drainage system regions were derived from a local mass concentration analysis of NASA-Deutsches Zentrum für Luftund Raumfahrt Gravity Recovery and Climate Experiment (GRACE mission) observations. From 2003 to 2005, the ice sheet lost 101 +/- 16 gigaton/year, with a gain of 54 gigaton/year above 2000 meters and a loss of 155 gigaton/year at lower elevations. The lower elevations show a large seasonal cycle, with mass losses during summer melting followed by gains from fall through spring. The overall rate of loss reflects a considerable change in trend (-113 +/- 17 gigaton/year) from a near balance during the 1990s but is smaller than some other recent estimates.

Journal Article↗
PubMed2005

Phase diagrams for cohesive particle mixing and segregation.

By taking a discrete view of cohesion, we develop a particle-level model which can accurately predict the extent of particle mixing and segregation in cohesive (wet) granular systems. Our model is based on a discrete characterization tool and is used to generate phase diagrams of the predicted particle behavior. These phase diagrams exhibit both mixed and segregated phases where the boundary is determined by the mechanical and surface properties of the particles, such that manipulation of surface properties and/or size/density ratios provides a method to control cohesive particle mixing and segregation. A detailed description of the phase diagram development process as well as quantitative validation of the theoretical results are reported here.

Journal Article↗
PubMed2004

Large scale association analysis for identification of genes underlying premature coronary heart disease: cumulative perspective from analysis of 111 candidate genes.

BACKGROUND: to date, only three groups have reported data from large scale genetic association studies of coronary heart disease using a case control design. METHODS AND RESULTS: to extend our initial report of 62 genes, we present data for 210 polymorphisms in 111 candidate genes genotyped in 352 white subjects with familial, premature coronary heart disease (onset age for men, 45; for women, 50) and a random sample of 418 population based whites. Multivariate logistic regression analysis was used to compare the distributions of genotypes between cases and the comparison group while controlling for age, sex, body mass, diabetes, and hypertension. Significant associations were found with polymorphisms in thrombospondin-4 (THBS4), thrombospondin-2 (THBS2) and plasminogen activator inhibitor-2 (PAI2), the strongest being with the A387P variant in THBS4 (p = 0.002). The THBS2 and THBS4 associations have since been replicated. We evaluated polymorphisms in 40 genes previously associated with coronary heart disease and found significant (p<0.05) associations with 10: ACE, APOE, F7, FGB, GP1BA, IL1RN, LRP1, MTHFR, SELP, and THPO. For five of these genes, the polymorphism associated in our study was different from that previously reported, suggesting linkage disequilibrium as an explanation for failure to replicate associations consistently across studies. We found strong linkage disequilibrium between polymorphisms within and between genes, especially on chromosome 1q22-q25, a region containing several candidate genes. CONCLUSIONS: despite known caveats of genetic association studies, they can be an effective means of hypothesis generation and complement classic linkage studies for understanding the genetic basis of coronary heart disease.

Adult↗
PubMed2003

Controlling cohesive particle mixing and segregation.

We observe experimentally that particle systems that would otherwise mix can be made to segregate and vice versa simply by adding moisture. Using a newly developed theoretical approach, we generate phase diagrams that exhibit both mixed and segregated phases and show how the location of phase boundaries may be manipulated via modifying the mechanical and surface properties of the particles. These results have implications for industrial mixing/separation processes as well as novel particle production methods (e.g., engineered agglomerates with precisely prescribed compositions).

Journal Article↗
PubMed2001

Melastatin expression and prognosis in cutaneous malignant melanoma.

PURPOSE: Melastatin (MLSN-1), a novel melanocyte-specific gene recently identified using a genomic approach, is expressed in murine and human melanoma cells at levels inversely proportional to metastatic rates in vivo. We studied the relationship between expression of melastatin mRNA in the primary cutaneous tumor and prognosis in patients with localized malignant melanoma. PATIENTS AND METHODS: Melastatin mRNA was evaluated by in situ hybridization in primary cutaneous melanoma from 150 patients with localized disease (American Joint Committee on Cancer [AJCC] stage I and II). Multivariate Cox proportional hazards regression analysis was performed to assess the prognostic utility of melastatin mRNA expression while adjusting for other prognostic indicators. RESULTS: Uniform melastatin mRNA expression in the primary tumor was correlated with prolonged disease-free survival (P < .0001). Multivariate analysis revealed that melastatin status, mitotic rate, and tumor thickness influence disease-free survival independently. The 8-year disease-free survival rate in AJCC stage I patients whose tumors diffusely expressed melastatin mRNA was 100%, whereas in stage I patients with melastatin loss, the disease-free survival rate was 77% +/- 15% (median +/- SE). In patients with stage II disease whose tumors diffusely expressed melastatin mRNA, the 8-year disease-free survival rate was 90% +/- 7%, whereas in patients with melastatin loss, the disease-free survival rate was 51% +/- 8%. CONCLUSION: Downregulation of melastatin mRNA in the primary cutaneous tumor is a prognostic marker for metastasis in patients with localized malignant melanoma and is independent of tumor thickness and other variables. Used in combination, melastatin status and tumor thickness allow for the identification of subgroups of patients at high and low risk of developing metastatic disease.

Adult↗
PubMed2001

Multiprotein complex formation at the beta myosin heavy chain distal muscle CAT element correlates with slow muscle expression but not mechanical overload responsiveness.

To examine the role of the beta-myosin heavy chain (betaMyHC) distal muscle CAT (MCAT) element in muscle fiber type-specific expression and mechanical overload (MOV) responsiveness, we conducted transgenic and in vitro experiments. In adult transgenic mice, mutation of the distal MCAT element led to significant reductions in chloramphenicol acetyltransferase (CAT) specific activity measured in control soleus and plantaris muscles when compared with wild type transgene beta293WT but did not abolish MOV-induced CAT specific activity. Electrophoretic mobility shift assay revealed the formation of a specific low migrating nuclear protein complex (LMC) at the betaMyHC MCAT element that was highly enriched only when using either MOV plantaris or control soleus nuclear extract. Scanning mutagenesis of the betaMyHC distal MCAT element revealed that only the nucleotides comprising the core MCAT element were essential for LMC formation. The proteins within the LMC when using either MOV plantaris or control soleus nuclear extracts were antigenically related to nominal transcription enhancer factor 1 (NTEF-1), poly(ADP-ribose) polymerase (PARP), and Max. Only in vitro translated TEF-1 protein bound to the distal MCAT element, suggesting that this multiprotein complex is tethered to the DNA via TEF-1. Protein-protein interaction assays revealed interactions between nominal TEF-1, PARP, and Max. Our studies show that for transgene beta293 the distal MCAT element is not required for MOV responsiveness but suggest that a multiprotein complex likely comprised of nominal TEF-1, PARP, and Max forms at this element to contribute to basal slow fiber expression.

Animals↗
PubMed2001

Personalized medicine: revolutionizing drug discovery and patient care.

Advances in human genome research are opening the door to a new paradigm for practising medicine that promises to transform healthcare. Personalized medicine, the use of marker-assisted diagnosis and targeted therapies derived from an individual's molecular profile, will impact the way drugs are developed and medicine is practiced. Knowledge of the molecular basis of disease will lead to novel target identification, toxicogenomic markers to screen compounds and improved selection of clinical trial patients, which will fundamentally change the pharmaceutical industry. The traditional linear process of drug discovery and development will be replaced by an integrated and heuristic approach. In addition, patient care will be revolutionized through the use of novel molecular predisposition, screening, diagnostic, prognostic, pharmacogenomic and monitoring markers. Although numerous challenges will need to be met to make personalized medicine a reality, with time, this approach will replace the traditional trial-and-error practice of medicine.

Drug Design↗
PubMed2001

Hepatitis C in methadone maintenance patients: prevalence and public policy implications.

OBJECTIVE: This study measured the extent and examined implications of hepatitis C (HCV) infection in a methadone maintenance treatment (MMT) population. METHOD: Four hundred and sixty patients were tested for HCV-Ab, hepatic enzymes and bilirubin, HCV-RNA, and hepatitis B antibody. RESULTS: Overall, 87% of this population had evidence of HCV-Ab. Among drug injectors (IDU), 96% were HCV-Ab positive. Among a subset of Laotian opium-smoking patients prevalence was only 11%. Sixty-two percent of patients with HCV-Ab had detectable HCV-RNA. Only 41% had elevated hepatic enzymes, and 5% had elevated bilirubin levels. All age groups were equally infected. Systemic problems in screening and treating HCV in drug users were identified. CONCLUSION: HCV infection poses significant long-term health risks for this population. Harm reduction interventions aimed at reducing transmission of HCV and other needle-related infectious disease deserves more consideration.

Adult↗
PubMed2001

Management of leg length inequality.

Leg length inequality is common. Treatment objectives include obtaining leg length equality, producing a level pelvis, and improving function. Clinical assessment should include determination of a level pelvis with the patient standing using a set of blocks of various heights to estimate the amount of leg length inequality. Radiographic measures include the teleroentgenogram, orthoradiograph, and computed tomography (CT). A prediction of the ultimate leg length inequality at skeletal maturity will be needed to determine treatment. Our guidelines for treatment of leg length inequality are as follows: <2 cm--no treatment or a lift in the shoe; 2 to 6 cm--an epiphysiodesis or shortening procedure is considered; 6 to 15 cm--a lengthening procedure is considered. A leg length inequality of 15 to 20 cm--may require a staged lengthening, lengthening combined with epiphysiodesis, or amputation. Numerous complications of limb lengthening procedures occur frequently, even in experienced hands.

Bone Lengthening↗
PubMed2000

The relationship between tight hamstrings and lumbar hypolordosis in children with cerebral palsy.

STUDY DESIGN: Retrospective clinical and radiographic review. OBJECTIVE: To assess the influence of tight hamstrings on the sagittal alignment of the thoracic and lumbar spine in children with cerebral palsy. SUMMARY OF BACKGROUND DATA: It is postulated that tight hamstrings may produce a hypolordosis of the lumbar spine. The abnormal sagittal contour of the spine may lead to increased stresses in the lumbar spine and subsequent pain and disability. This is of special concern in children with cerebral palsy who often have shortened spastic hamstring muscles. METHODS: Twenty-one patients were evaluated, with a mean age of 9.4 years. Standing and sitting lateral spine films were obtained and the lumbar lordosis and thoracic kyphosis were measured using the Cobb method. The popliteal angle was measured to assess hamstring tightness, such that a large popliteal angle indicates tight hamstrings. RESULTS: We found a statistically significant correlation between the sitting lumbar curve and popliteal angle (Pearson correlation value -0.77, P < 0.01). As the popliteal angle increased, the amount of lumbar lordosis decreased. This correlation was less significant when the patient was standing (Pearson correlation value -0.59). CONCLUSION: This study demonstrates that there is a correlation between tight hamstrings, as measured by the popliteal angle, and decreasing lumbar lordosis, especially when sitting.

Adolescent↗
PubMed2000

The use of single-nucleotide polymorphism maps in pharmacogenomics.

Single-nucleotide polymorphisms (SNPs), common variations among the DNA of individuals, are being uncovered and assembled into large SNP databases that promise to enable the dissection of the genetic basis of disease and drug response (i.e., pharmacogenomics). Although great strides have been made in understanding the diversity of the human genome, such as the frequency, distribution, and type of genetic variation that exists, the feasibility of applying this information to uncover useful pharmacogenomic markers is uncertain. The health care industry is clamoring for access to SNP databases for use in research in the hope of revolutionizing the drug development process. As the reality of using SNPs to uncover drug response markers is rarely addressed, this review discusses practical issues, such as patient sample size, SNP density and genome coverage, and data interpretation, that will be important for determining the applicability of pharmacogenomic information to medical practice.

Databases, Factual↗
PubMed2000

Methadone levels in human milk.

Pregnant women on methadone maintenance therapy frequently want to nurse yet are often discouraged from doing so because of concern about the amount of methadone that may be in the breast milk. This study analyzed the levels of methadone in the milk of nursing mothers and compared these levels to those in other published reports. Fourteen breast milk samples were obtained from 8 women maintained on methadone doses of 25 to 180 mg/day. Methadone levels in milk ranged from 27 to 260 ng/ml, with a mean level for the group of 95 ng/ml. The mean daily methadone ingestion, based on a newborn intake of 475 ml/day of breast milk, was 0.05 mg/day. This level is small and consistent with those in other published reports. Breastfeeding duration ranged from 2.5 to 21 months. There were no adverse events associated with breastfeeding or weaning. This study supports the compatibility of breastfeeding and methadone maintenance therapy.

Female↗
PubMed2000

Fibular hemimelia: comparison of outcome measurments after amputation and lengthening.

BACKGROUND: Treatment of fibular hemimelia includes either Syme or Boyd amputation with early prosthetic fitting or tibial lengthening. Numerous studies have documented the success of both procedures. The purpose of our study was to compare the outcome after amputation with that after tibial lengthening, specifically with regard to activity restrictions, pain, satisfaction, complications, number of procedures, and cost, in children with fibular hemimelia. METHODS: Thirty limbs in twenty-five patients treated with either an amputation or a lengthening procedure and followed for at least two years were studied. Fifteen patients underwent amputation, and ten patients underwent lengthening of the tibia. The mean age was 1.2 years at the time of amputation and 9.7 years at the time of initial lengthening. The mean duration of follow-up was 6.9 years after the amputations and 7.1 years after the lengthening procedures. RESULTS: The patients who underwent amputation were able to perform more activities than those who had a lengthening (mean activity score, 0 compared with 1.2 points; p<0.05), and they had less pain (mean pain score, 0.2 compared with 1.2 points; p = 0.091), were more satisfied and had a lower complication rate (0.37 compared with 1.91; p<0.05). The patients who underwent amputation also had fewer procedures (1.9 compared with 7.0; p<0.05), at a lower cost ($7016 compared with $26,900; p<0.05), than those who had a lengthening. Lengthening was successful in equalizing limb lengths; the mean limb-length discrepancy, assessed in nine of eleven limbs, was 0.7 centimeter. CONCLUSIONS: This study demonstrated that children who undergo early amputation are more active, have less pain, are more satisfied, have fewer complications, undergo fewer procedures, and incur less cost than those who undergo lengthening. This was true even though good results were obtained with the lengthening procedures and most patients achieved limb-length equality, were able to walk, had minimal pain, and were quite active.

Adolescent↗
PubMed1999

Nuclear protein binding at the beta-myosin heavy chain A/T-rich element is enriched following increased skeletal muscle activity.

In adult mouse skeletal muscle, beta-myosin heavy chain (betaMyHC) gene expression is primarily restricted to slow-type I fibers but can be induced in fast-type II fibers by mechanical overload (MOV). Our previous transgenic analyses have delimited an 89-base pair (bp) MOV-responsive region (-293 to -205), and shown that mutation of the MCAT and C-rich elements within this region did not abolish betaMyHC transgene induction by MOV. In this study we describe an A/T-rich element (betaA/T-rich; -269 5'-GGAGATATTTTT-3' -258) located within this 89-bp region that, only under MOV conditions, revealed enriched binding as characterized by electrophoretic mobility shift assays and dimethyl sulfate and diethyl pyrocarbonate interference footprinting. Direct, competition, and supershift electrophoretic mobility shift assays revealed highly enriched specific binding activity at the betaA/T-rich element that was antigenically distinct from GATA-4, MEF2A-D, SRF, and Oct-1, nuclear proteins that were previously shown to bind A/T-rich elements. In vitro translated GATA-4, MEF2C, SRF, and Oct-1 bound to consensus GATA, MEF2, SRE, and Oct-1 elements, respectively, but not to the betaA/T-rich element. Two-dimensional UV cross-linking of the bromodeoxyuridine-substituted betaA/T-rich element with mechanically overloaded plantaris (MOV-P) nuclear extract detected two proteins (44 and 48 kDa). Our results indicate that the betaA/T-rich element may function in vivo as a betaMyHC MOV-inducible element during hypertrophy of adult skeletal muscle by binding two distinct proteins identified only in MOV-P nuclear extract.

AT Rich Sequence↗