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Thomas P Meehan

Publications and source records attributed to Thomas P Meehan.

At least 19 recordsLinked to original sources
PubMed2006

Point mutations in the melanocortin-4 receptor cause variable obesity in mice.

Mutations in the melanocortin-4 receptor (MC4R) are associated with early-onset obesity in humans. Furthermore, a null Mc4r allele in mice leads to severe obesity due to hyperphagia and decreased energy expenditure. As part of independent N-ethyl- N-nitrosourea (ENU) mutagenesis screens, two obesity mutants, Fatboy and Southbeach, were isolated. Mapping revealed linkage to the melanocortin-4 receptor (Mc4r) and sequencing found single amino acid changes in Mc4r for each line. Expression of the mutant receptors in HEK 293 cells revealed defects in receptor signaling. The mutated Fatboy receptor (I194T) shows an increase in the effective concentration necessary for 50% of maximal signaling (EC(50)) when stimulated with alpha-MSH. Based on competitive binding, I194T is expressed on the cell surface at lower levels than the nonmutated receptor. In contrast, Southbeach (L300P) displays minimal receptor signaling when stimulated with the natural ligand alpha-MSH or the synthetic agonist NDP-alpha-MSH. Cell surface binding is absent, which usually indicates a lack of cell surface expression. However, antibody binding to Flag-tagged receptors by flow cytometry analysis and immunofluorescence demonstrates that L300P is translocated to the plasma membrane at a level comparable to the wild-type receptor. These results indicate a correlation with remaining receptor activity and the severity of the obesity in the mice homozygous for the mutations. Southbeach has less receptor activity and becomes more obese. These mutants will serve as good models for the variability in phenotype in humans carrying mutations in the MC4R gene.

Alkylating Agents↗
PubMed2006

Isolation of Salmonella enterica and Shiga-toxigenic Escherichia coli O157 from feces of animals in public contact areas of United States zoological parks.

The fecal prevalence of subclinical Salmonella enterica and Shiga-toxigenic Escherichia coli O157 among animals in human-animal contact exhibits at institutions in the United States accredited by the Association of Zoos and Aquariums was estimated to assess public health risk. The prevalence was less than 0.6% for both zoonotic pathogens among 997 animals sampled at 36 exhibits.

Animals↗
PubMed2006

Constitutively active luteinizing hormone receptors: consequences of in vivo expression.

Activating mutations in the luteinizing hormone receptor (LHR) gene are one of the most common mutations found in the gonadotropin receptor genes. Human males with these mutations exhibit precocious puberty while females do not have an obvious phenotype. To better understand the pathophysiology of premature LHR activation, transgenic mice have been generated with an activating mutation in LHR and a genetically engineered ligand-activated LHR. This review will summarize the major findings obtained with these two genetically modified mouse models and briefly discuss the similarities and differences between them and with the human phenotype.

Animals↗
PubMed2006

Phenotypic characterization of Bbs4 null mice reveals age-dependent penetrance and variable expressivity.

Bardet-Biedl syndrome (BBS) is a rare oligogenic disorder exhibiting both clinical and genetic heterogeneity. Although the BBS phenotype is variable both between and within families, the syndrome is characterized by the hallmarks of developmental and learning difficulties, post-axial polydactylia, obesity, hypogenitalism, renal abnormalities, retinal dystrophy, and several less frequently observed features. Eleven genes mutated in BBS patients have been identified, and more are expected to exist, since about 20-30% of all families cannot be explained by the known loci. To investigate the etiopathogenesis of BBS, we created a mouse null for one of the murine homologues, Bbs4, to assess the contribution of one gene to the pleiotropic murine Bbs phenotype. Bbs4 null mice, although initially runted compared to their littermates, ultimately become obese in a gender-dependent manner, females earlier and with more severity than males. Blood chemistry tests indicated abnormal lipid profiles, signs of liver dysfunction, and elevated insulin and leptin levels reminiscent of metabolic syndrome. As in patients with BBS, we found age-dependent retinal dystrophy. Behavioral assessment revealed that mutant mice displayed more anxiety-related responses and reduced social dominance. We noted the rare occurrence of birth defects, including neural tube defects and hydrometrocolpos, in the null mice. Evaluations of these null mice have uncovered phenotypic features with age-dependent penetrance and variable expressivity, partially recapitulating the human BBS phenotype.

Aging↗
PubMed2006

Improving the quality of preventive cardiovascular care provided by primary care physicians: insights from a US Quality Improvement Organization.

BACKGROUND: During 2000-03, Qualidigm, a US Quality Improvement Organization, conducted a project to improve the care received by elderly Medicare patients with coronary artery disease or cardiovascular risk factors. METHODS: We recruited primary care physicians in private practice in the state of Connecticut. Then, we identified approximately 30-50 patients per physician from the periods 1 January 2000 to 31 December 2000 and 1 November 2001 to 31 October 2002. We abstracted medical records to assess processes and outcomes of care, and we provided the physicians with performance data and a variety of practice-enhancing materials. The physicians utilized those materials that they perceived to be most helpful. RESULTS: We identified and recruited 974 primary care physicians to participate. Of these, 103 (10.6%) committed to participate, and 85 of the 103 completed the project. Among the intervention tools, physicians and their office personnel utilized personal digital assistants (PDAs) (36.5%) and patient education materials (34.1%) most commonly. Overall, quality of care improved for most physicians (mean quality score 62.0 to 67.8%, P < 0.001). However, not all improved, and most improvements were modest [mean absolute improvement in quality score 5.8%, standard deviation (SD) 6.8%]. CONCLUSIONS: Quality Improvement Organizations and others interested in improving outpatient quality of care face significant challenges in recruiting self-employed primary care physicians to quality improvement projects and in bringing about transformational change. Future primary care quality improvement projects should include careful assessments of practice-specific barriers, interventions that are linked to these barriers, and support of the practices on implementation.

Aged↗
PubMed2006

Promoting physicians' self-assessment and quality improvement: the ABIM diabetes practice improvement module.

INTRODUCTION: The American Board of Internal Medicine (ABIM) recognized that certification and recertification must be based on an assessment of performance in practice as well as an examination of medical knowledge. Physician self-assessment of practice performance is proposed as one method that certification boards may use to evaluate competence in practice-based learning and improvement and systems-based practice. METHODS: Sixteen practicing general internists and endocrinologists with 10-year time-limited certification participated in a beta test of the ABIM's diabetes practice improvement module (PIM) as part of their recertification program. A PIM consists of a self-directed medical record audit, practice system survey, and patient survey. A quality improvement education specialist from the Connecticut Quality Improvement Organization provided on-site and distance consultation on quality improvement methods and tools. An independent audit assessed the reliability of physician self-audit. Qualitative interviews were conducted at 2 time points to assess for physician satisfaction and behavioral change in quality improvement. RESULTS: Fourteen physicians completed the diabetes PIM. All but 1 physician found the medical record audit to provide important information about the practice. Of the 11 physicians who completed a follow-up interview, 10 stated that the quality improvement education specialist helped improve their practice. DISCUSSION: Self-assessment using the ABIM diabetes PIM as part of recertification provides valuable practice information and can lead to meaningful behavioral change by physicians. Collaboration with an educator in quality improvement appears to facilitate the effects of the practice improvement module. Future work should investigate the effect on patient outcomes.

Adult↗
PubMed2006

The effects of patient volume on the quality of diabetic care for Medicare beneficiaries.

BACKGROUND: The quality of care for Medicare beneficiaries with diabetes remains suboptimal. The contributing factors at the physician level are not well characterized, especially the relationship of patient volume and physician performance. OBJECTIVE: We sought to determine associations between the number of Medicare diabetic patients cared for by a primary care physician and the receipt of important diabetic processes of care. DESIGN: Physicians were grouped into quintiles based on the number of Medicare patients with diabetes. Hierarchical generalized linear models were used to examine associations between number of patients, frequency of visits, physician experience, patient factors and the receipt of diabetes processes of care using Part A and B Medicare claims data for 2001. PARTICIPANTS AND PATIENTS: All Connecticut primary care physicians who cared for Medicare fee-for-service beneficiaries with diabetes in 2001. MAIN OUTCOME MEASURES: The main outcome measures were associations of the receipt of diabetes process of care measures with the number of diabetic Medicare patients in a physician practice panel, adjusted for frequency of visits, patient comorbidity, age, ethnicity, and physician experience. RESULTS: Patients in the highest volume physician quintile were significantly more likely to have received hemoglobin A1c measurements, lipid profiles, and retinal eye examinations than patients in the lowest physician quintile in 2001, even after adjustment for multiple factors. For each step up in quintile volume group among primary care physicians, the increased odds of receiving a hemoglobin A1c measurement was 1.16 (95% confidence interval [CI] 1.10-1.23), 1.12 (95% CI 1.07-1.18) for a lipid profile, 1.06 (95% CI 1.02-1.09) for a retinal eye examination, and 1.48 (95% CI 1.22-1.81) for receiving all 3 measures. CONCLUSIONS: This study suggests that Medicare fee-for-service patients with diabetes cared for by physicians with greater numbers of diabetic Medicare patients in their practice are more likely to receive important diabetes processes of care.

Aged↗
PubMed2006

Factors associated with the hospitalization of low-risk patients with community-acquired pneumonia in a cluster-randomized trial.

BACKGROUND: Many low-risk patients with pneumonia are hospitalized despite recommendations to treat such patients in the outpatient setting. OBJECTIVE: To identify the factors associated with the hospitalization of low-risk patients with pneumonia. METHODS: We analyzed data collected by retrospective chart review for 1,889 low-risk patients (Pneumonia Severity Index [PSI] risk classes I to III without evidence of arterial oxygen desaturation) enrolled in a cluster-randomized trial conducted in 32 emergency departments. RESULTS: Overall, 845 (44.7%) of all low-risk patients were treated as inpatients. Factors independently associated with an increased odds of hospitalization included PSI risk classes II and III, the presence of medical or psychosocial contraindications to outpatient treatment, comorbid conditions that were not contained in the PSI (cognitive impairment, history of coronary artery disease, diabetes mellitus, or pulmonary disease), multilobar radiographic infiltrates, and home therapy with oxygen, corticosteroids, or antibiotics before presentation. While 32.8% of low-risk inpatients had a contraindication to outpatient treatment and 47.1% had one or more preexisting treatments, comorbid conditions, or radiographic abnormalities not contained in the PSI, 20.1% had no identifiable risk factors for hospitalization other than PSI risk class II or III. CONCLUSIONS: Hospital admission appears justified for one-third of low-risk inpatients based upon the presence of one or more contraindications to outpatient treatment. At least one-fifth of low-risk inpatients did not have a contraindication to outpatient treatment or an identifiable risk factor for hospitalization, suggesting that treatment of a larger proportion of such low-risk patients in the outpatient setting could be achieved without adversely affecting patient outcomes.

Cluster Analysis↗
PubMed2006

Profiling variations in outpatient care for Medicare beneficiaries in Connecticut.

Qualidigm, the Medicare Quality Improvement Organization for Connecticut, is reporting the rates of four outpatient services for Medicare beneficiaries on its website (www.qualidigm.org). These measures include screening for breast cancer (mammography) and chronic disease management for diabetes (HbAlc, eye exam and lipid profile). Maps of Connecticut illustrate the rates for Whites and Non-whites by Health Service Area. The maps highlight variation across small local areas and between Whites and Non-whites. By reporting these rates publicly, Qualidigm hopes to facilitate ongoing efforts by community organizations and health care providers to make improvements in care, especially for the underserved populations throughout the state.

Ambulatory Care↗
PubMed2005

Effect of increasing the intensity of implementing pneumonia guidelines: a randomized, controlled trial.

BACKGROUND: Despite the development of evidence-based pneumonia guidelines, limited data exist on the most effective means to implement guideline recommendations into clinical practice. OBJECTIVE: To compare the effectiveness and safety of 3 guideline implementation strategies. DESIGN: Cluster-randomized, controlled trial. SETTING: 32 emergency departments in Pennsylvania and Connecticut. PATIENTS: 3219 patients with a clinical and radiographic diagnosis of pneumonia. INTERVENTIONS: The authors implemented a project-developed guideline for the initial site of treatment based on the Pneumonia Severity Index and performance of evidence-based processes of care at the emergency department level. Guideline implementation strategies were defined as low (n = 8), moderate (n = 12), and high intensity (n = 12). MEASUREMENTS: Effectiveness outcomes were the rate at which low-risk patients were treated on an outpatient basis and the performance of recommended processes of care. Safety outcomes included death, subsequent hospitalization for outpatients, and medical complications for inpatients. RESULTS: More low-risk patients (n = 1901) were treated as outpatients in the moderate-intensity and high-intensity groups than in the low-intensity group (high-intensity group, 61.9%; moderate-intensity group, 61.0%; low-intensity group, 37.5%; P = 0.004). More outpatients (n = 1125) in the high-intensity group received all 4 recommended processes of care (high-intensity group, 60.9%; moderate-intensity group, 28.3%; low-intensity group, 25.3%; P < 0.001); more inpatients (n = 2076) in the high-intensity group received all 4 recommended processes of care (high-intensity group, 44.3%; moderate-intensity group, 30.1%; low-intensity group, 23.0%; P < 0.001). No statistically significant differences in safety outcomes were observed across interventions. LIMITATIONS: Twenty percent of eligible patients were not enrolled, and data on effectiveness outcomes were not collected before the trial. CONCLUSIONS: Both moderate-intensity and high-intensity guideline implementation strategies safely increased the proportion of low-risk patients with pneumonia who were treated as outpatients. The high-intensity strategy was most effective for increasing the performance of the recommended processes of care for outpatients and inpatients.

Aged↗
PubMed2005

Prospective comparison of three validated prediction rules for prognosis in community-acquired pneumonia.

PURPOSE: We assessed the performance of 3 validated prognostic rules in predicting 30-day mortality in community-acquired pneumonia: the 20 variable Pneumonia Severity Index and the easier to calculate CURB (confusion, urea nitrogen, respiratory rate, blood pressure) and CURB-65 severity scores. SUBJECTS AND METHODS: We prospectively followed 3181 patients with community-acquired pneumonia from 32 hospital emergency departments (January-December 2001) and assessed mortality 30 days after initial presentation. Patients were stratified into Pneumonia Severity Index risk classes (I-V) and CURB (0-4) and CURB-65 (0-5) risk strata. We compared the discriminatory power (area under the receiver operating characteristic curve) of these rules to predict mortality and their accuracy based on sensitivity, specificity, predictive values, and likelihood ratios. RESULTS: The Pneumonia Severity Index (risk classes I-III) classified a greater proportion of patients as low risk (68% [2152/3181]) than either a CURB score <1 (51% [1635/3181]) or a CURB-65 score <2 (61% [1952/3181]). Low-risk patients identified based on the Pneumonia Severity Index had a slightly lower mortality (1.4% [31/2152]) than patients classified as low-risk based on the CURB (1.7% [28/1635]) or the CURB-65 (1.7% [33/1952]). The area under the receiver operating characteristic curve was higher for the Pneumonia Severity Index (0.81) than for either the CURB (0.73) or CURB-65 (0.76) scores (P <0.001, for each pairwise comparison). At comparable cut-points, the Pneumonia Severity Index had a higher sensitivity and a somewhat higher negative predictive value for mortality than either CURB score. CONCLUSIONS: The more complex Pneumonia Severity Index has a higher discriminatory power for short-term mortality, defines a greater proportion of patients at low risk, and is slightly more accurate in identifying patients at low risk than either CURB score.

Aged↗
PubMed2005

Using randomized controlled trial data, the agreement between retrospectively and prospectively collected data comprising the pneumonia severity index was substantial.

OBJECTIVE: To assess the agreement between prospectively and retrospectively determined variables comprising the Pneumonia Severity Index (PSI), assignment to PSI risk class, and designation as low risk, based on these two methods of data collection. STUDY DESIGN AND SETTING: We analyzed data from a randomized trial of patients with community-acquired pneumonia managed in 32 hospital emergency departments (EDs). For all enrolled patients, the 20 PSI variables were collected prospectively by ED providers and retrospectively by medical record abstractors. We examined the agreement for each of the 20 PSI variables, assignment to the five PSI risk classes, and classification of patients as low (classes I-III) vs. high (classes IV and V) risk. Agreement was measured using total percent agreement and the kappa statistic. RESULTS: Among the 3,220 enrolled patients, percent agreement was >90% for 18 of the 20 variables comprising the PSI, with most unweighted kappa's being >0.6. Agreement was substantial for assignment to PSI risk class (percent agreement: 92.7%; weighted kappa: 0.79) and for classification as low vs. high risk (percent agreement: 88.5%; unweighted kappa: 0.74). CONCLUSION: There was substantial agreement between retrospective and prospective assignment to PSI risk class, classification as low vs. high risk, and the determination of most individual variables that constitute the PSI.

Adolescent↗
PubMed2005

What have we learned about how to measure quality of care for patients with community-acquired pneumonia?

The most commonly used measures of quality of care for hospitalized pneumonia patients are process measures as opposed to outcome measures.For a process measure to be useful in assessing quality of care, it must be linked to a desired outcome. For patients hospitalized with pneumonia, the obtaining of blood cultures, the timely use of appropriate antibiotics, and the delivery of the influenza and pneumococcal vaccines are the process measures most widely used for assessing quality of care in relation to clinical outcomes. The admission decision and the length of time that intravenous antibiotics are used are process measurements that directly affect financial outcomes.

Anti-Bacterial Agents↗
PubMed2005

Structure-function relationships of the luteinizing hormone receptor.

Of the 800-900 genes in the human genome that appear to encode G-protein-coupled receptors (GPCRs), two are known to encode receptors that bind the three heterodimeric human gonadotropins, luteinizing hormone (LH), chorionic gonadotropin (CG), and follicle-stimulating hormone (FSH). LH and CG bind to a common receptor, LHR, and FSH binds to a paralogous receptor. These GPCRs contain a relatively large ectodomain (ECD), responsible for high-affinity ligand binding, and a transmembrane portion, as in the other GPCRs. The ECD contains nine leucine-rich repeats capped by N-terminal and C-terminal cysteine-rich regions. The overall goal of this research is to elucidate the molecular mechanisms by which CG and LH bind to and activate LHR and the latter, in turn, activates Gs alpha. A combination of molecular modeling and site-directed mutagenesis, coupled with binding and signaling studies in transiently transfected HEK 293 cells expressing wild-type and mutant forms of LHR, has been used to develop and test models for the LHR ECD, the CG-LHR ECD complex, and the structural changes in the transmembrane helices and intracellular loops, particularly loop 2, that accompany receptor activation. In addition, a single-chain CG-LHR complex was designed in which a fusion protein of the two subunits of human CG was linked to full-length LHR. This ligand-receptor complex was shown to be constitutively active in cellular models and in transgenic mice, the latter of which exhibit precocious puberty. From a combination of molecular modeling, site-directed mutagenesis, genetic/protein engineering, and receptor characterization in cellular and animal models, considerable insight is being developed on the mechanisms of normal and aberrant activation of LHR.

Animals↗
PubMed2005

Gonadal defects and hormonal alterations in transgenic mice expressing a single chain human chorionic gonadotropin-lutropin receptor complex.

To study the effects of premature and chronic ligand-mediated luteinizing hormone receptor (LHR) activation on reproductive development, we have generated transgenic mice expressing a genetically engineered, constitutively active yoked hormone-receptor complex (YHR), in which a fusion protein of human chorionic gonadotropin (hCG) is covalently linked to the N-terminus of rat LHR. YHR-expressing mice (YHR(+)) were analyzed at pre- and post-pubertal ages. Relative to wild type (WT) controls, male mice exhibited prepubertal increases in testosterone levels and seminal vesicle weights, and decreases in serum FSH, serum LH, testes weight, and the size of the seminiferous tubules. In adult male YHR(+) mice, testosterone and LH levels are not significantly different from WT controls. However, FSH levels and testes weights remain decreased. Female YHR(+) mice undergo precocious puberty with early vaginal opening, accelerated uterine development, enhanced follicular development, including the presence of corpora lutea, and an increase in serum progesterone. At 12 weeks of age, the ovary exhibits a relative increase in the amount of interstitial tissue, comprised of cells that are hypertrophic and luteinized, as well as follicles that are degenerating. Additionally, hemorrhagic cysts develop in approximately 25% of the transgenic mice. These degenerative changes are consistent with an aging ovary suggesting that CG-induced LHR activation in female mice leads to precocious sexual development and ovarian lesions. Taken together, these data indicate that the single chain YHR is functional in vivo and demonstrate that YHR(+) mice provide a novel system to further understand the reproductive consequences of aberrant LHR activation.

Age Factors↗
PubMed2004

Genetically distant American Canine distemper virus lineages have recently caused epizootics with somewhat different characteristics in raccoons living around a large suburban zoo in the USA.

BACKGROUND: Mortality rates have differed during distemper outbreaks among free-ranging raccoons (Procyon lotor) living around a large Chicago-area zoo, and appeared higher in year 2001 than in 1998 and 2000. We hypothesized that a more lethal variant of the local Canine distemper virus (CDV) lineage had emerged in 2001, and sought the genetic basis that led to increased virulence. However, a more complex model surfaced during preliminary analyses of CDV genomic sequences in infected tissues and of virus isolated in vitro from the raccoons. RESULTS: Phylogenetic analyses of subgenomic CDV fusion (F) -, phosphoprotein (P) -, and complete hemagglutinin (H) - gene sequences indicated that distinct American CDV lineages caused the distemper epizootics. The 1998 outbreak was caused by viruses that are likely from an old CDV lineage that includes CDV Snyder Hill and Lederle, which are CDV strains from the early 1950's. The 2000 and 2001 viruses appear to stem from the lineage of CDV A75/17, which was isolated in the mid 1970's. Only the 2001 viruses formed large syncytia in brain and/or lung tissue, and during primary isolation in-vitro in Vero cells, demonstrating at least one phenotypic property by which they differed from the other viruses. CONCLUSIONS: Two different American CDV lineages caused the raccoon distemper outbreaks. The 1998 viruses are genetically distant to the 2000/2001 viruses. Since CDV does not cause persistent infections, the cycling of different CDV lineages within the same locale suggests multiple reintroductions of the virus to area raccoons. Our findings establish a precedent for determining whether the perceived differences in mortality rates are actual and attributable in part to inherent differences between CDV strains arising from different CDV lineages.

Amino Acid Sequence↗