Dissecting the "black box" of community intervention: lessons from community-wide cardiovascular disease prevention programs in the US and Sweden.
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Adult↗
Biomedical subjects
C Lewis
Publications and source records attributed to C Lewis.
Association of complementation group and mutation type with clinical outcome in fanconi anemia. European Fanconi Anemia Research Group.
Fanconi anemia (FA) is a clinically and genetically heterogeneous disorder. Clinical care is complicated by variable age at onset and severity of hematologic symptoms. Recent advances in the molecular biology of FA have allowed us to investigate the relationship between FA genotype and the nature and severity of the clinical phenotype. Two hundred forty-five patients from all 7 known complementation groups (FA-A to FA-G) were studied. Mutations were detected in one of the cloned FANC genes in 169 patients; in the remainder the complementation group was assigned by cell fusion or Western blotting. A range of qualitative and quantitative clinical parameters was compared for each complementation group and for different classes of mutation. Significant phenotypic differences were found. FA-G patients had more severe cytopenia and a higher incidence of leukemia. Somatic abnormalities were less prevalent in FA-C, but more common in the rare groups FA-D, FA-E, and FA-F. In FA-A, patients homozygous for null mutations had an earlier onset of anemia and a higher incidence of leukemia than those with mutations producing an altered protein. In FA-C, there was a later age of onset of aplastic anemia and fewer somatic abnormalities in patients with the 322delG mutation, but there were more somatic abnormalities in patients with IVS4 + 4A --> T. This study indicates that FA patients with mutations in the FANCG gene and patients homozygous for null mutations in FANCA are high-risk groups with a poor hematologic outcome and should be considered as candidates both for frequent monitoring and early therapeutic intervention. (Blood. 2000;96:4064-4070)
Abnormalities, Multiple↗
Insights from a large rural population laboratory. Health census '89 and '99.
PURPOSE: Data are limited on health status behaviors and use of health services for rural residents. Yet rural areas now have higher rates of chronic diseases, such as coronary heart disease, than urban areas.METHODS: A population laboratory (Health Census) was established in rural Central NY (Otsego County) to study these variables in this population. HC '89 was a door-to-door enumeration of all permanent households in the country. In 1989, 44,500 adults in 18,000 households provided data on individual health screenings, cancer and cardiovascular risk factors, health behaviors, chronic disease, access to care, preventive services use, health insurance and emergency department utilization. Data collection for HC '99 will identify 10-year trends; it also includes baseline data for children. Also, households in six surrounding rural counties (N = 10,000) were sampled; cost benefits of different survey methods were assessed. Questions about perceived health status, and special health and pediatric preventive care needs were included. After 10 years of social change, many limitations of traditional survey methods became apparent; much more varied and frequent types of follow-up were needed to achieve adequate response rates.RESULTS: The HC '89 final response rate was 86%. There were significant socioeconomic gradients in use of preventive services (blood pressure screening, rectal exams, mammograms and Pap smears). Adults without health insurance or Medicaid had much lower utilization rates of screening tests and higher rates of cigarette smoking and obesity. Several community intervention programs were implemented as a result of HC '89. HC '99 provides additional analyses to examine change in preventive service use, self-reported chronic disease, and health services use; it will likely verify the persistence of socioeconomic gradients. Response rates are similar to '89, but achieved only with more intensive reinforcement.CONCLUSIONS: HC '89 confirmed a lag in positive health indices in rural populations in Central NY. Both newer methodologies now needed and results of HC '99 will serve as guides for smaller rural counties to develop affordable local health surveys and plan intervention strategies.
Journal Article↗
Crystal structure of the IMP-1 metallo beta-lactamase from Pseudomonas aeruginosa and its complex with a mercaptocarboxylate inhibitor: binding determinants of a potent, broad-spectrum inhibitor.
Metallo beta-lactamase enzymes confer antibiotic resistance to bacteria by catalyzing the hydrolysis of beta-lactam antibiotics. This relatively new form of resistance is spreading unchallenged as there is a current lack of potent and selective inhibitors of metallo beta-lactamases. Reported here are the crystal structures of the native IMP-1 metallo beta-lactamase from Pseudomonas aeruginosa and its complex with a mercaptocarboxylate inhibitor, 2-[5-(1-tetrazolylmethyl)thien-3-yl]-N-[2-(mercaptomethyl)-4 -(phenylb utyrylglycine)]. The structures were determined by molecular replacement, and refined to 3.1 A (native) and 2.0 A (complex) resolution. Binding of the inhibitor in the active site induces a conformational change that results in closing of the flap and transforms the active site groove into a tunnel-shaped cavity enclosing 83% of the solvent accessible surface area of the inhibitor. The inhibitor binds in the active site through interactions with residues that are conserved among metallo beta-lactamases; the inhibitor's carboxylate group interacts with Lys161, and the main chain amide nitrogen of Asn167. In the "oxyanion hole", the amide carbonyl oxygen of the inhibitor interacts through a water molecule with the side chain of Asn167, the inhibitor's thiolate bridges the two Zn(II) ions in the active site displacing the bridging water, and the phenylbutyryl side chain binds in a hydrophobic pocket (S1) at the base of the flap. The flap is displaced 2.9 A compared to the unbound structure, allowing Trp28 to interact edge-to-face with the inhibitor's thiophene ring. The similarities between this inhibitor and the beta-lactam substrates suggest a mode of substrate binding and the role of the conserved residues in the active site. It appears that the metallo beta-lactamases bind their substrates by establishing a subset of binding interactions near the catalytic center with conserved characteristic chemical groups of the beta-lactam substrates. These interactions are complemented by additional nonspecific binding between the more variable groups in the substrates and the flexible flap. This unique mode of binding of the mercaptocarboxylate inhibitor in the enzyme active site provides a binding model for metallo beta-lactamase inhibition with utility for future drug design.
Binding Sites↗
Representation of the cardinality principle: early conception of error in a counterfactual test.
There is debate over how the integration of non-verbal quantifying and verbal counting relates to the representation of number principles. A stringent representational test would be one in which a child obeyed a number principle where it ran counter to a characteristic procedure. We devised a test relying on the uniqueness principle for using evidence from a miscount in inferring a counterfactual cardinal number. All the 5-year-olds passed, as did half the preschoolers. Subtests probed associated number-skills. We suggest that a crucial preschool step is to start conceptualising error by categorising relations between counting and miscounting. That step is taken at a similar age to passing a representational theory of mind test but the two were uncorrelated.
Child Development↗
Correlates of physicians' prevention-related practices. Findings from the Women Physicians' Health Study.
BACKGROUND: Determinants of physicians' prevention-related counseling and screening practices are not well understood. Such determinants are worth knowing because we can then intervene on malleable variables and produce physicians with stronger prevention-related skills. Of the few such variables that have been examined, they have typically only been studied in univariate analyses or in small or otherwise limited populations and have been especially sparsely studied in women physicians. OBJECTIVE: To explore the effect of potential counseling- and screening-related variables in 4501 respondents to the Women Physicians' Health Study, a questionnaire-based study of a representative sample of US women MDs. RESULTS: Being a primary care practitioner and practicing a related health habit oneself were significantly correlated with reporting counseling and screening for all prevention-related variables examined. Current attempts to improve a related habit oneself, ethnicity, region, practice site, and amount of continuing medical education were sometimes significantly correlated with counseling and screening; most other variables studied (i.e., personal health status, a personal or family history of disease, control of work environment, and career satisfaction) were rarely significantly correlated. CONCLUSIONS: Being a primary care practitioner and having related healthy habits oneself were the most significant correlates of US women physicians' self-reported prevention-related counseling and screening practices. These findings suggest potential new directions for physician training.
Adult↗
Bronchiectasis in Alaska Native children: causes and clinical courses.
Although bronchiectasis has become a rare condition in U.S. children, it is still commonly diagnosed in Alaska Native children in the Yukon Kuskokwim Delta. The prevalence of bronchiectasis has not decreased in persons born during the 1980s as compared with those born in the 1940s. We reviewed case histories of 46 children with bronchiectasis. We observed that recurrent pneumonia was the major preceding medical condition in 85% of patients. There was an association between the lobes affected by pneumonia and the lobes affected by bronchiectasis. Eight (17%) patients had surgical resection of involved lobes. We conclude that the continued high prevalence of bronchiectasis appears to be related to extremely high rates of infant and childhood pneumonia. Pediatr Pulmonol. 2000;29:182-187. Published 2000 Wiley-Liss, Inc.
Adolescent↗
Large-scale purification of myeloperoxidase from HL60 promyelocytic cells: characterization and comparison to human neutrophil myeloperoxidase.
A large-scale purification procedure was developed for the isolation of myeloperoxidase from HL60 promyelocytic cells in culture. Initial studies showed the bulk of peroxidase-positive myeloperoxidase activity to be located in the cetyltrimethylammonium bromide solubilized particulate fraction of cell homogenates. The myeloperoxidase was then chromatographically purified using concanavalin A followed by gel filtration. SDS-PAGE analysis of the final preparation showed the presence of only two proteins with molecular masses of approximately 55 and 15 kDa, corresponding to the large and small subunits of myeloperoxidase. These data, along with Reinheit Zahl (RZ) values (A(430)/A(280)) of greater than or equal to 0.72, indicate that the myeloperoxidase prepared by this method is apparently homogeneous. Preparations routinely yielded 12-20 mg of pure myeloperoxidase per 10 ml of cell pellet. The HL60 myeloperoxidase was shown to be indistinguishable from purified human neutrophil myeloperoxidase by size exclusion chromatography, analytical ultracentrifugation, SDS-PAGE, Western blot, and NH(2)-terminal sequence analysis. The activities of the two myeloperoxidase samples, as measured using either the tetramethylbenzidine or the taurine chloramine assay, were indistinguishable. Finally, both enzymes responded identically to dapsone and aminobenzoic acid hydrazide, known inhibitors of myeloperoxidase. A protocol is presented here for the rapid, large-scale purification of myeloperoxidase from cultured HL60 cells, as well as evidence for the interchangeability of this myeloperoxidase and that purified from human neutrophils.
Benzidines↗
Does hypertension and its pharmacotherapy affect the quality of sexual function in women?
Considerable research has been conducted into the effects of antihypertensive drugs on male sexual functioning. This remains underexplored in women, even though almost half of treated hypertensives are women. An ambulatory medical record-based, case-control study was designed to study sexual function in treated and untreated hypertensive women and healthy controls. We conducted this study at a teaching hospital with satellite clinics in upstate New York. Of 3312 medical records reviewed, 640 premenopausal white women with or without mild hypertension (defined as blood pressure [BP] > or = 140/90 and < 160/110 mmHg), in heterosexual relationships, with no other significant medical history, were eligible. Of these, 241 women agreed to participate, and 224 (35%) completed both a self-administered questionnaire and a telephone interview. Analysis was conducted on 211 women (107 healthy controls, and 104 mild hypertensives, of whom 37 were unmedicated and 67 medicated). Questions on sexuality were classified into seven composite variables and later further divided. There were no demographic differences between participants and nonparticipants. Cases and controls differed only by age (P < .01); therefore, subsequent analysis was age-adjusted. Current smokers reported a significantly lower mean score for orgasm than did nonsmokers (P = .04). Women with unmedicated and medicated hypertension did not differ significantly on sexuality scores and were subsequently combined. Using age-adjusted ANOVA, women with hypertension reported significantly decreased lubrication and orgasm and increased pain compared to nonhypertensive women. There were no significant differences by ANOVA in the quality of sexual functioning between six treatment groups. In conclusion, the quality of female sexual functioning was quantified in an ambulatory outpatient setting. Hypertensive women, regardless of type of treatment, reported age-adjusted decrease in vaginal lubrication, less frequent orgasm, and more frequent pain when compared to nonhypertensive women. Emotional aspects of sexual functioning in hypertensive women do not appear to be impaired. These areas require further investigation. An incidental finding indicated diminished orgasm reported in current smokers, compared to nonsmokers, which was not associated with age or hypertension.
Adult↗
Epidemiology of erectile dysfunction: a community-based study in rural New York State.
PURPOSE: Few published population-based studies that deal with the prevalence of erectile dysfunction (ED) involve rural populations. This study determined the prevalence and determinants of ED among a rural population. It also evaluated the relevance of some major predictors of help-seeking decisions. METHODS: A self-administered survey was conducted by mail among 5198 randomly selected men 50-76 years old, living in four rural counties in Central New York State. RESULTS: The response rate was 44.7% and the participation rate among respondents was 71.0%. Mean ages of men reporting and those not reporting ED were 64.5 7.2 and 59.8 7.2 years respectively. The mean duration of self-reported ED was 4.9 4.6 years. The overall prevalence of ED was 46.3% while the minimum prevalence was estimated as 21.3%. Age-specific prevalence was 26.0%, 34.9%, 46.9%, 57.8% and 69.4% among men 50-54, 55-59, 60-64, 65-69, and 70-76 years old respectively. There was a statistically significant relationship between age, socio-economic status, perceived state of health and erectile function status (p < 0.001). However, socio-economic status, marital status, perceived state of health and age were not significant predictors of help-seeking decisions. CONCLUSIONS: The prevalence of ED among men 50-76 years old in rural Central New York State is at least 21.3% and may be as high as 46.3%. Age, perceived state of health and socio-economic status were found to be important determinants of erectile dysfunction among this population. For purposes of comparative analyses, future epidemiological studies should report both the overall and minimum rates among men with clinically relevant erectile dysfunction.
Aged↗
Stability and haplotype analysis of the FRAXE region.
FRAXE full mutations are rare and appear to be associated with mild mental retardation. As part of a screening survey of boys with learning difficulties to determine the frequency of full and premutations, we have collected data on the frequency of instability at FRAXE for about 4000 transmissions and the haplotype for over 7000 chromosomes. The distribution of FRAXE repeats was similar to other English populations but differed from two North American Caucasian series. Observed instability at FRAXE was rare but increased with increasing repeat number, and there were no expansions into the full mutation range, except in pedigrees ascertained through a full mutation. Haplotype analysis suggested division into five groups with each group having a characteristic distribution of FRAXE repeats. Fourteen of the 15 full mutations occurred on a single haplotype and this haplotype also had a significant excess of intermediate-sized alleles, suggesting that full mutations originate from large normal alleles. However, a related haplotype also had a significant excess of intermediates but we observed no full mutations on this haplotype, suggesting either loss or gain of stability determinants on it. We suggest that whilst triplet repeat size is a significant predisposing factor for expansion at FRAXE other genetic determinants are also likely to be important.
Alleles↗
The macrophage - a novel system to deliver gene therapy to pathological hypoxia.
The use of activated macrophages in the treatment of cancer has been largely ineffectual. By 'arming' these cells with the ability to express a therapeutic gene we demonstrate significant advances in the efficacy of this approach. We have used a hypoxia-regulated adenoviral vector to transduce human macrophages with either a reporter or a therapeutic gene encoding human cytochrome P4502B6 (CYP2B6). Infiltration of transduced macrophages into a tumour spheroid results in induction of gene expression. We demonstrate significant tumour cell killing only in the presence of cyclophosphamide via activation by P4502B6 and show that this can be further targeted to tumours through hypoxia regulated gene expression. Gene Therapy (2000) 7, 255-262.
Adenoviridae↗
A phase II trial of paclitaxel and epirubicin in advanced breast cancer.
Initial trials of paclitaxel and doxorubicin in advanced breast cancer yielded high response rates but significant cardiac toxicity was observed. In this phase II trial we investigated the efficacy and safety of paclitaxel combined with epirubicin. Patients with advanced breast cancer, performance status 0-2, measurable disease, and a normal left ventricular ejection fraction, who may have received adjuvant chemotherapy were treated with epirubicin 75 mg m(-2) followed by a 3-h infusion of paclitaxel 175 mg m(-2) repeated every 3 weeks. Forty-three eligible patients were treated at six centres. 67% patients received the maximum of six cycles. The response rate was 54% (95% CI 38-69%), 12% CR and 42% PR. Estimated median progression-free survival was 6.9 months (95% CI 5.4-10.0) and estimated median overall survival was 17.9 months (95% CI 14.2-25.7). Four patients had a decrease in the left ventricular ejection fraction (LVEF) of > or =20% of baseline value, and in two patients the LVEF decreased to below the lower limit of normal, but no patient developed clinical evidence of cardiac failure. Grade 4 neutropenia occurred in 56% cycles, but only 4% of cycles were complicated by febrile neutropenia. Grade 3 or 4 non-haematologic toxicity was uncommon. In conclusion, paclitaxel 175 mg m(-2) and epirubicin 75 mg m(-2) is a well tolerated, promising regimen for the treatment of advanced breast cancer.
Adult↗
Higher brain blood flow at amygdala and lower frontal cortex blood flow in PTSD patients with comorbid cocaine and alcohol abuse compared with normals.
Posttraumatic stress disorder (PTSD) patients with histories of cocaine and alcohol abuse (CA-PTSD) were compared with normal volunteers. Positron emission tomography (PET) scans with 15O-butanol were used to compare regional cerebral blood flow (rCBF) between the groups during rest and during an auditory continuous performance task (ACPT). CA-PTSD patients had significantly higher rCBF in right amygdala and left parahippocampal gyrus than normals during the ACPT. Normals had higher rCBF at frontal cortex during the resting scan and during the ACPT. The role of the amygdala in attention and fear conditioning suggests that increased amygdala rCBF may be related to clinical features of PTSD. Cocaine use may be associated with increased amygdala rCBF in PTSD patients. Amygdala and frontal cortex attention system components may be reciprocally related and their relative contributions to processing of neutral stimuli perturbed in CA-PTSD.
Adult↗
Celiac disease and human leukocyte antigen genotype: accuracy of diagnosis in self-diagnosed individuals, dosage effect, and sibling risk.
BACKGROUND: Celiac disease is an autoimmune disorder of the small intestine characterized by intolerance to gluten. Traditionally, diagnosis is made by intestinal biopsy. Testing for immunoglobulin (Ig) A endomysial antibodies in the serum also is used for diagnosis. Biopsy and serology revert to normal with adherence to a gluten-free diet. Often, after an index case is diagnosed, siblings with symptoms adhere to a gluten-free diet without biopsy or serologic confirmation. More than 90% of patients with celiac disease have the human leukocyte antigen (HLA) DQA1*0501-DQB1*0201 genotype. Non-HLA genes also have been implicated. METHODS: One hundred ninety-five individuals with confirmed or suspected celiac disease were identified in 73 families affected by the disease. IgA endomysial antibody testing was performed for all symptomatic family members who did not have biopsy-confirmed diagnoses. DNA samples were genotyped at D6S276 and the HLA class II loci DQA and DQB. RESULTS: At the time sampling was begun in families, 88 of 177 (49.7%) individuals were self-diagnosed and adhering to a gluten-free diet. Ninety percent (91/101) of confirmed cases (biopsy or serology) had at least 1 copy of the DQA1*0501-DQB1*0201 genotype, whereas only 67% (46/69) of cases self-diagnosed (adherence to gluten-free diet without confirmation) had at least 1 copy. Of confirmed cases, 61% carried two copies of DQB*0201. It is estimated that the HLA association and other unlinked genes contribute approximately equally to the sibling risk of celiac disease. CONCLUSIONS: A dosage effect of DQB1*0201 may be associated with an increased risk of celiac disease. Self-diagnosis of celiac disease is as common as confirmed diagnosis in families in the United States. Diagnosis of celiac disease on the basis of clinical response to gluten restriction is inaccurate. With long-term adherence to a gluten-free diet, serologic test results are likely to be negative. Based on HLA genotype, approximately one third of self-diagnosed individuals are unlikely to have celiac disease. However, it is not possible to determine which individuals consuming a gluten-free diet have the disease. Therefore, before starting a gluten-free diet, serologic screening and biopsy confirmation are necessary.
Biopsy↗
EMCyberSchool: an evaluation of computer-assisted instruction on the Internet.
OBJECTIVES: To test the hypothesis that integration of the EMCyberSchool, a computer-assisted instruction (CAI) tool available on the Internet, into the curriculum of a senior medical student subinternship in emergency medicine (EM) would improve exam scores and course satisfaction. METHODS: Students were prospectively randomized, by four-week blocks, into a CAI group and a no-CAI group. All students were surveyed on previous computer experience and their use and opinion of the EMCyberSchool. RESULTS: Completed data were obtained from 100 of 120 students. Sixty-five percent of the students said they wanted CAI as an adjunct to their course curricula; only 28% actually used the educational tool. The students who used the site rated it useful (4.2/5), easy to use (4.4/5), and easy to access (4.1/5). Of the students who had access, and chose not to use the EMCyberSchool, 77.8% reported not having enough time as the reason for not using the site. The mean exam scores were 72.8% for the students in the CAI group and 68.2% for those in the no-CAI group (p = 0.058). In the CAI group, 77.5% (31/40) of the students rated the course as outstanding or excellent; compared with 66% (33/50) in the no-CAI group (p = 0.23). CONCLUSIONS: Although desired, it remains unclear whether CAI on the Internet is a useful adjunct for teaching EM to medical students.
Clinical Clerkship↗
FRAXA and FRAXE: the results of a five year survey.
We report the results of a five year survey of FRAXA and FRAXE mutations among boys aged 5 to 18 with special educational needs (SEN) related to learning disability. We tested their mothers using the X chromosome not transmitted to the son as a control chromosome, and the X chromosome inherited by the son to provide information on stability of transmission. We tested 3738 boys and 2968 mothers and found 20 FRAXA and one FRAXE full mutations among the boys and none among the mothers. This gives an estimated prevalence of full mutations in males of 1 in 5530 for FRAXA and 1 in 23 423 for FRAXE. We found an excess of intermediate and premutation alleles for both FRAXA and FRAXE. For FRAXA this was significant at the 0.001 level but the excess for FRAXE was significant only at the 0.03 level. We conclude that the excess of intermediate and premutation sized alleles for FRAXA may well be a contributing factor to the boys' mental impairment, while that for FRAXE may be a chance finding. We studied approximately 3000 transmissions from mother to son and found five instabilities of FRAXA in the common or intermediate range and three instabilities of FRAXE in the intermediate range. Thus instabilities in trinucleotide repeat size for FRAXA and FRAXE are rare, especially among alleles in the common size range.
Adolescent↗