Clinical and molecular delineation of the 17q21.31 microdeletion syndrome.

BACKGROUND: The chromosome 17q21.31 microdeletion syndrome is a novel genomic disorder that has originally been identified using high resolution genome analyses in patients with unexplained mental retardation. AIM: We report the molecular and/or clinical characterisation of 22 individuals with the 17q21.31 microdeletion syndrome. RESULTS: We estimate the prevalence of the syndrome to be 1 in 16,000 and show that it is highly underdiagnosed. Extensive clinical examination reveals that developmental delay, hypotonia, facial dysmorphisms including a long face, a tubular or pear-shaped nose and a bulbous nasal tip, and a friendly/amiable behaviour are the most characteristic features. Other clinically important features include epilepsy, heart defects and kidney/urologic anomalies. Using high resolution oligonucleotide arrays we narrow the 17q21.31 critical region to a 424 kb genomic segment (chr17: 41046729-41470954, hg17) encompassing at least six genes, among which is the gene encoding microtubule associated protein tau (MAPT). Mutation screening of MAPT in 122 individuals with a phenotype suggestive of 17q21.31 deletion carriers, but who do not carry the recurrent deletion, failed to identify any disease associated variants. In five deletion carriers we identify a <500 bp rearrangement hotspot at the proximal breakpoint contained within an L2 LINE motif and show that in every case examined the parent originating the deletion carries a common 900 kb 17q21.31 inversion polymorphism, indicating that this inversion is a necessary factor for deletion to occur (p<10(-5)). CONCLUSION: Our data establish the 17q21.31 microdeletion syndrome as a clinically and molecularly well recognisable genomic disorder.

Medicaid reimbursement for prenatal smoking intervention influences quitting and cessation.

BACKGROUND: 40% of births in the USA are covered by Medicaid and smoking is prevalent among recipients. The objective of this study was to evaluate the association between levels of Medicaid coverage for prenatal smoking cessation interventions on quitting during pregnancy and maintaining cessation after delivery. METHODS: Population based survey study of 7513 post-partum women from 15 states who: participated in Pregnancy Risk Assessment Monitoring System (PRAMS) during 1998-2000; smoked at the beginning of their pregnancy; and had Medicaid coverage. Participating states were categorised into three levels of Medicaid coverage for smoking cessation interventions during prenatal care: extensive (pharmacotherapies and counselling); some (pharmacotherapies or counselling); or none. Quit rates among women who smoked before pregnancy and rates of maintaining cessation were examined. RESULTS: Higher levels of coverage during prenatal care for smoking cessation interventions were associated with higher quit rates; 51%, 43%, and 39% of women quit in states with extensive, some, and no coverage, respectively. Compared to women in states with no coverage, women in states with extensive coverage had 1.6 times the odds of quitting smoking (odds ratio (OR) 1.58, 95% confidence interval (CI) 1.00 to 2.49). Maintenance of cessation after delivery was associated with extensive levels of Medicaid coverage; 48% of women maintained cessation in states with extensive coverage compared to 37% of women in states with no coverage. Compared to women in states with no coverage, women with extensive coverage had 1.6 times the odds of maintaining cessation (OR 1.63, 95% CI 1.04 to 2.56). CONCLUSIONS: Prenatal Medicaid coverage for both pharmacotherapies and counselling is associated with higher rates of quitting and continued cessation. This suggests policymakers can promote cessation by broadening smoking cessation services in Medicaid prenatal coverage.

Who decides? Physicians' willingness to use life-sustaining treatment.

BACKGROUND: Physician specialty training is associated with variations in the use of medical treatment for specific diseases. OBJECTIVE: To examine whether physicians' specialties predict differences in willingness to use life-sustaining treatments. METHODS: One hundred fifty-eight physicians (response rate, 85%) who cared for 378 hospitalized patients with end-stage congestive heart failure, chronic obstructive pulmonary disease, malignant neoplasms, or hepatic cirrhosis were interviewed to assess their thresholds for use of specific life-sustaining treatments. Their patients were then followed up to determine whether decisions were made to use or withhold cardiopulmonary resuscitation, ventilator support, or intensive care. Physicians' attitudes, their stated thresholds for treatment use, and their use of these treatments in daily practice were compared by specialty group. RESULTS: Physicians recommended cardiopulmonary resuscitation and ventilator support for patients with end-stage congestive heart failure or chronic obstructive pulmonary disease if the chance for survival was at lease 48%, but they required a predicted survival of at least 74% for patients with cancer. For a patient with end-stage congestive heart failure or chronic obstructive pulmonary disease, cardiologists were consistently more willing than other physicians to use life-sustaining treatments. In practice, decisions to use or withhold such treatments were made for 151 patients with end-stage diseases. Compared with other physicians, cardiologists were least likely to issue orders to withhold treatment and most likely to use life-sustaining treatments for patients they treated. Oncologists rarely used such treatments and issued orders to withhold these treatments much more often. CONCLUSION: Physician specialty is associated with differences in willingness to use, and in actual use of, life-sustaining treatments.

Factors responsible for immunizations referrals to health departments in North Carolina.

BACKGROUND: Despite the existence of Medicaid and other programs designed to eliminate cost as a barrier to immunization in physicians' offices, referrals to local health departments for immunizations are common. Many children leave their physicians' offices without receiving needed immunizations. PURPOSE: To determine: 1) the frequency and determinants of immunization referrals to health departments in North Carolina, and 2) the factors associated with private physicians' decisions to immunize Medicaid children in their offices and participate in the state-funded vaccine replacement program. METHODS: The 2537 pediatricians and family physicians licensed in North Carolina were surveyed by mail using a 23-item, self-administered questionnaire. RESULTS: Seventy-two percent of physicians responded; 93% referred at least some children to local health departments for immunizations. Concern regarding parents' ability to pay for immunizations was the most important reason for referral for 93% of respondents. Forty percent referred all or some of their Medicaid patients; excessive paperwork, inadequate reimbursement, and parental preferences were the most common reasons. Only 33% of physicians had participated in the state's vaccine replacement program. Family physicians, and physicians in solo or two-physician practices in rural counties, and in practices caring for a small number of children on Medicaid were most likely to refer children covered by Medicaid and not participate in the state's existing vaccine replacement program. CONCLUSIONS: Medicaid and North Carolina's vaccine replacement program are not preventing large numbers of immunization referrals to health departments. Future programs designed to increase the proportion of children immunized in physicians' offices will not succeed if more effective incentives for physician participation are not developed.

Older Medicare enrolees' choices for insured services.

OBJECTIVES: The Medicare Trust Fund is expected to be bankrupt in the next decade, thus threatening the viability of the Medicare Program. We have ascertained what Medicare enrollees' priorities for insured services would be, and why, if it were fiscally necessary to limit Medicare benefits to maintain the viability of the Program. DESIGN: A cross-sectional survey using anonymous, inperson interviews and an innovative instrument to elicit choices. SETTING: General Internal Medicine outpatient clinic at a university teaching hospital. PARTICIPANTS: One hundred five adults, 65 years of age and older, who had primary care physician visits between July and September 1995. MEASUREMENTS: Desire to personally select insurance benefits, insurance benefit choices, and the reasons for selection or rejection of benefits. RESULTS: Subjects of various educational and economic backgrounds were able to carry out the selection process with relative case, and four-fifths of respondents preferred to make their own choices about insured services. The most frequently selected services were hospitalization, outpatient care, prescription drugs, eye care, and home care, in descending order. Subjects selected 52 different combinations of services. Only 2% of respondents picked the current Medicare service package. The reasons given for selection varied by service; cost and current or anticipated need for a service were the most frequently cited forces driving the choices made. CONCLUSION: These data suggest that Medicare enrollees prefer some element of choice about their health insurance coverage. Their choices vary widely and differ from the current Medicare package.

Preventive services received by adolescents with cystic fibrosis and sickle cell disease.

OBJECTIVE: To determine the proportion of adolescents with cystic fibrosis (CF) or sickle cell disease (SCD) who reported speaking with their physicians about health-promoting and risky behaviors and whether the rate of discussions varied by whether the main physician was a primary care provider or specialist. HYPOTHESIS: Adolescents reporting a primary care provider as their main physician would be more likely to have received risk behavior counseling and other preventive services. DESIGN: Survey. SETTING: Comprehensive CF and SCD centers in 5 North Carolina referral hospitals. PARTICIPANTS: Three hundred twenty-one (74%) of 437 adolescents aged 12 through 19 years (mean age, 15.6 years; 51% male) with CF or SCD identified through center registries. MAIN OUTCOME MEASURES: Sources of health care, main physician, and recall of discussions with physicians regarding sexual issues, substance use, weight or dieting, safety issues, depression, and violence. RESULTS: Adolescents with CF (53%) or SCD (46%) most commonly reported a specialist as their main physician. For those (83%) who saw their main physician in the past year, adolescents with SCD reported counseling rates ranging from 43% for sexuality to 15% for weapon carrying or fighting. For adolescents with CF, rates ranged from 65% for weight and dieting to 30% for sexuality and 6% for weapon carrying or fighting. Adolescents whose main physician was a primary care provider were no more or less likely to report counseling for any topic (all P>.05). CONCLUSIONS: Physicians, regardless of specialty, infrequently discussed common behavioral issues with these adolescents with CF or SCD. A coordinated effort between primary care physicians and specialists may be helpful in delivering optimal preventive services to this population.

Interactive computer technology for skin cancer prevention targeting children.

BACKGROUND: Computer technology has become an integral part of health care, yet there have been few studies exploring the use of multimedia technology in the prevention of cancer, especially targeting children. OBJECTIVE: The aims of this study were to develop and evaluate a new multimedia computer program for the primary prevention of skin cancer among a childhood population. DESIGN AND PARTICIPANTS: An interactive CD-ROM program was developed, then pilot tested in a public elementary school in rural North Carolina. This intervention trial involved 8 third- and fourth-grade classes (N = 209 students), randomized into 3 groups: computer intervention, standard teacher-led intervention, and controls. MAIN OUTCOME MEASURES: Students were tested using pre- and postintervention surveys that measured knowledge, attitudes, and self-reported behaviors. A 7-month follow-up survey was performed. RESULTS: There was a significant increase in postintervention knowledge for the computer group when compared to either the teacher-led or control groups (mean scores out of 100: 75.2, 59.5, 55.0, respectively; p < 0.001). Attitudes about suntanning demonstrated a significant difference between the 3 groups (mean scores out of 100: 64.0, 53.0, 48.6, respectively; p = 0.002). There were slight improvements in the behavioral scores, especially among the computer group, but the overall differences were not significant. Similar overall results were found for the long-term follow-up survey, except that attitudes about suntanning no longer demonstrated a significant difference. CONCLUSION: These results indicate that this new educational tool is an effective way to introduce health education programs for young children in typical classroom settings. This prototype may serve as a model for the development of future preventive school-based programs, including applications to other conditions associated with high-risk behaviors among children.

Comparison of physical activity in adolescents with cystic fibrosis versus age-matched controls.

The aims of this study were to compare self-reported vigorous physical activity and participation in sports among adolescents with cystic fibrosis (CF) to those of age matched peers from the general population, and to determine which CF patient characteristics are associated with regular physical activity. One hundred and sixteen of 141 (82%) adolescents aged 12-19 years identified through North Carolina CF Care Center registries confidentially completed a self-administered questionnaire (the CDC's Youth Risk Behavior Survey) addressing health-compromising and health-enhancing behaviors, including physical activity. They were age- and gender-matched to adolescents from North Carolina schools who completed the same survey. Adolescents with CF did not differ significantly from their matched peers with regard to participating three or more times a week in activities that "make you sweat or breathe hard" (63% vs. 67%, P = 0.37), physical education class (59% vs. 61%, P = 0.81), or team sports (52% vs. 61%, P = 0.10). For all categories of activity, participation declined among adolescents aged 17 years or older. After adjusting for gender and health status, early (14 years or younger) and middle (15-16 years) adolescents were more likely to participate in all three types of activity than older adolescents with CF. Like their peers in the general population, adolescents aged 17 and older are much less likely to report regular physical activity, or participation in physical education class or in team sports. Healthcare providers should be aware of this decline in activity in late adolescence and should consider efforts to maintain physical activity among older teenagers and young adults.

The urban epidemiology of recurrent injury: beyond age, race, and gender stereotypes.

OBJECTIVES: To profile all patients presenting to an urban ED with any injury, and to determine whether the rate of subsequent injury treated in the ED varied by demographic and E-code (external mechanism of injury) category. The hypothesis that young black males were disproportionately at risk for re-injury was addressed. METHODS: A cohort of consecutive patients presenting to an urban ED with any injury between January 1, 1991, and November 31, 1992, were followed prospectively for 1 year from their index visit dates. Any repeat ED visits due to injury were sought. The mean number of injury visits per year (the total number of ED injury visits for each patient divided by 1 year) was computed for the overall population and by race, age, gender, and E-code. RESULTS: The sample consisted of 34,378 patients who made 44,813 visits to the ED for injury. Of these patients, 22% had a repeat injury in 1 year, with a cohort mean of 1.30 injury visits per year. This mean did not vary appreciably by race (black 1.33, white 1.27), age (1-17 yr, 1.21; 18-24 yr, 1.32; 25-64 yr, 1.34; > 65 yr, 1.23), gender (males 1.33, females 1.27), or E-code category. Having a prior injury visit in the preceding year was the best predictor of future injury (mean repeat visit rate = 2.08). CONCLUSIONS: When examining patients presenting with any injury to an urban ED, the mean numbers of injury visits are remarkably similar across demographic and E-code categories. Although there are factors that place patients at risk for recurrent injury, those factors are not demographic-all patients presenting to an ED with injury should be considered at risk for re-injury.

Beyond the good prognosis. Examination of an inception cohort of patients with chronic low back pain.

STUDY DESIGN: A 22-month prospective cohort study. OBJECTIVES: To describe the course of an inception cohort of patients with chronic low back pain. SUMMARY OF BACKGROUND DATA: Chronic low back pain is a debilitating condition with great medical and social cost. METHODS: A cohort of 1246 patients with acute low back pain who sought treatment from 208 North Carolina providers was observed. Patients who developed chronic low back pain were identified. Entry criteria were back pain of less than 10 weeks' duration, no previous care for this episode of low back pain, no previous spine surgery, not pregnant, no nonskin malignancy, and access to a telephone. The providers were of four types: primary care medical doctors, doctors of Chiropractic, orthopedic surgeons, and health maintenance organization-based primary care providers. Patients were contacted by telephone shortly after enrollment and at 2, 4, 8, 12, and 24 weeks, with a final interview at 22 months. Patient functional status, care-seeking, and satisfaction were evaluated. RESULTS: Ninety-six patients had chronic, continuous symptoms for 3 months, forming the inception cohort of chronic low back pain. A valid, reliable measure of back-specific functional disability also was used. Predictors of the development of chronicity were poor baseline functional status and sciatica. A more powerful predictor of chronicity was poor functional status at 4 weeks. Two thirds of patients with chronic low back pain at 3 months had functionally disabling symptoms at 22 months, and a majority of these were employed. Satisfaction with care was low. Forty-six patients (2.6% of the entire cohort) underwent surgery, with no statistically significant difference in surgical rates among initial provider strata. Patients who underwent surgery after 3 months had a Roland disability score at 22 months of 10 (7.7, 12.3). Forty-one percent of patients with chronic low back pain see an orthopedic or neurologic surgeon. Chronic low back pain occurs in 7.7% of patients who seek care for acute low back pain, with unremitting pain for 22 months in 4.7%. CONCLUSION: Once established, chronic low back pain is persistent. Most patients with chronic low back pain seek little care, and a majority are employed. Future research should emphasize maintenance of employment and function.

Physical therapy utilization by patients with acute low back pain.

BACKGROUND AND PURPOSE: The purposes of this study were (1) to describe the demographic and clinical characteristics of a group of patients with acute low back pain (LBP), (2) to describe those patients who were being treated by physical therapists, and (3) to analyze their use of physical therapy services. SUBJECTS: The study sample consisted of 1,580 patients with acute LBP who were treated by 208 practitioners in North Carolina. The initial providers were primary care physicians, chiropractors, orthopedic surgeons, and primary care providers at a health maintenance organization. METHODS: A telephone interview was conducted after the initial office visit to assess demographics and medical history, health care services utilization, and functional status. Follow-up telephone interviews were also conducted 2, 4, 8, 12, and 24 weeks later. RESULTS: One hundred ninety-nine (12.6%) of the subjects reported that they saw a physical therapist either by any provider referral or by direct access. Therapeutic exercise was the most commonly reported treatment procedure. Post-high-school education, receipt of Workers' Compensation, prior physical therapy for LBP, LBP and pain below the knee in one or both legs, and a higher baseline Roland-Morris Questionnaire score were associated with being treated by physical therapists. CONCLUSION AND DISCUSSION: In this study, physical therapists were utilized in the treatment of patients with greater severity of LBP. The findings demonstrate the importance of controlling for baseline characteristics when comparing outcomes of LBP when treated by different types of providers.

Characterization of AAT1: a gene involved in the regulation of amino acid transport in Saccharomyces cerevisiae.

A new class of Saccharomyces cerevisiae mutants (aat1 - amino acid transport) has been identified. These mutants are unable to grow on rich medium or on minimal medium supplemented with certain amino acids (isoleucine, methionine, phenylalanine, tyrosine or valine). This phenotype is directly linked to the presence of the leu2 allele in these strains: aat1 LEU2 organisms grow normally on all media tested. Leucine uptake through the leucine-specific permease is inhibited to less than 35% of wild-type levels in aat1 cells preincubated in nonpermissive media, and the activity of the general amino acid permease is also low in these conditions. aat1 cells are therefore unable to grow on rich media because they cannot take up enough leucine to supplement their auxotrophic requirement.

The control of morphogenesis in Saccharomyces cerevisiae by Elm1 kinase is responsive to RAS/cAMP pathway activity and tryptophan availability.

Many fungi undergo a morphological transition to filamentous growth in response to limiting nutrient conditions. Constitutively elongated Saccharomyces cerevisiae mutants (elm) have been isolated; the ELM1 gene encodes a putative serine/threonine protein kinase. A novel allele, elm1-15, has been isolated in an S288C-derived strain, which causes a pleiotropic phenotype, including media-specific growth effects, abnormal morphology and altered stress response, in cells that are auxotrophic for tryptophan. elm1-15 trp1 cells cannot use many nitrogen sources, are sensitive to amino acid analogues, have very low general amino acid permease activity and do not accumulate trehalose. In contrast, haploid elm1-15 TRP1 cells grow well in budding form on all media, are stress resistant and overaccumulate trehalose. Several lines of evidence suggest that Elm1 acts on functions related to the RAS/cAMP pathway. Overexpression of Elm1 partially rescues the ts phenotype of cdc25 and cyr1 mutants. Deletion of ELM1 in low PKA activity mutants increased the severity of their phenotypes, and activation of Ras2 decreases the cell elongation phenotype of elm1 mutants. A 'signal integration' model for the complex relationship of Elm1 and the RAS/cAMP pathway in controlling morphogenesis in response to nutrients is proposed.

The branched-chain amino acid permease gene of Saccharomyces cerevisiae, BAP2, encodes the high-affinity leucine permease (S1).

The amino acid leucine has been shown previously to be transported into a yeast cell by at least three permeases: the general amino acid permease, a high-affinity permease (S1) and a low-affinity permease (S2). We isolated the gene BAP2 as a multicopy suppressor of the YPD- phenotype of aat1leu2 yeast. BAP2 has been identified previously as encoding an amino acid permease which transports branched-chain amino acids. In order to align the genetic and biochemical studies of leucine uptake we completed a detailed kinetic analysis of yeast strains in which the BAP2 gene was disrupted and compared this to the kinetics of uptake of the parental strain. We demonstrate that BAP2 encodes the high-affinity leucine permease previously called S1.

Ethical issues in communicating science.

Most of the publicized work on scientific ethics concentrates on establishing professional norms and avoiding misconduct. The successful communication of science is the responsibility of all involved in the process. In one study, the increased incidence of autism and other social developmental disorders in males was investigated by examining individuals with Turner's syndrome (XO females). In the national newspaper this became "Genetic X-factor explains why boys will always be boys". The steps by which a study on developmental disorders, published in a highly prestigious journal, was transformed into an article in the science section which 'explained' the socially expected gender-based behavior of genetically normal children are fascinating and, unfortunately far too typical. The scientists wrote an excellent article that has just one sentence at the end that hesitantly suggests that the findings might, with further study, have some relevance to understanding normal behavior. The general interest article in the front of the journal gave a good account of the research, but suggested more strongly that there could be an in-built biological dimorphism in social cognition. This was misrepresented in the press as proof of gender differences that "undermines the trend towards sexual equality", and both illustrates cultural bias and provides fodder for feminist critiques of science. The study has been made to appear to be biased in favor of justifying the social structure of society, and yet it was the translation from the scientific study to national news that produced this transformation to biased genetic determinism. It is poor communication of the actual science, coupled with a lack of skepticism on the part of the public, that contributes to such a misapplication of science. Scientists should resist the urge to generalize their results to make them more compelling. The science community should not allow misconstructions of scientific facts to go unchallenged. Journalists, for both the scientific publication and the newspaper, should resist the inclination to embellish the finding with social significance that is not present. For their part, readers must be doubly skeptical of any finding that appears to underwrite any current social hierarchy. We are all responsible for a communication and interpretation of science that is as accurate and socially responsible as possible.

Lethal action of bacteriophage lambda S gene.

The functions of the bacteriophage lambda lysis genes S, R, and Rz were investigated. Different combinations of wild-type and inactive alleles of all three lysis genes were cloned into the plasmid pBH20 and were expressed under the control of a lac operator-promoter. The involvement of the Rz gene in lysis was proposed in our previous work and was confirmed by the Mg2+-dependent lysis defect of clones in which part of the Rz gene is deleted. Membrane vesicles prepared from induced S+ cells were shown to have a severely reduced capacity for active transport of glucose; this defect was detectable at least 20 min before lysis. Cell viability was also shown to decrease very soon after induction, long before physiological death and lysis; this decrease in viability is absolutely dependent on S expression and independent of R and Rz. The nonviable fraction of cells at any time after induction was demonstrated to be equal to the fraction committed to eventual lysis. Induction of an Sts clone showed that the S gene product is stable and capable of inducing lysis long after the cessation of synthesis of S gene product. A model for S action is proposed.

Thermal denaturation and coagulation of whey proteins: effect of sugars.

The thermal coagulation of unfractionated whey proteins was inhibited by various sugars. The disaccharides, sucrose and lactose, were most effective, and the amino sugar, glucosamine, least effective in this respect. Ultraviolet absorption and light-scattering measurements on the thermal denaturation and coagulation of both unfractionated and individual whey proteins (alpha-lactalbumin, beta-lactoglobulin, and bovine serum albumin) showed that sucrose promotes the denaturation of these proteins but inhibits their subsequent coagulation. These results are interpreted in terms of the effect of sucrose on the hydrophobic interactions between solvent and protein.