Regulatory T cell frequencies are increased in preterm infants with clinical early-onset sepsis.

The predisposition of preterm neonates to invasive infection is, as yet, incompletely understood. Regulatory T cells (Tregs ) are potential candidates for the ontogenetic control of immune activation and tissue damage in preterm infants. It was the aim of our study to characterize lymphocyte subsets and in particular CD4(+) CD25(+) forkhead box protein 3 (FoxP3)(+) Tregs in peripheral blood of well-phenotyped preterm infants (n = 117; 23 + 0 - 36 + 6 weeks of gestational age) in the first 3 days of life in comparison to term infants and adults. We demonstrated a negative correlation of Treg frequencies and gestational age. Tregs were increased in blood samples of preterm infants compared to term infants and adults. Notably, we found an increased Treg frequency in preterm infants with clinical early-onset sepsis while cause of preterm delivery, e.g. chorioamnionitis, did not affect Treg frequencies. Our data suggest that Tregs apparently play an important role in maintaining maternal-fetal tolerance, which turns into an increased sepsis risk after preterm delivery. Functional analyses are needed in order to elucidate whether Tregs have potential as future target for diagnostics and therapeutics.

Survival trends of Staphylococcus aureus, Pseudomonas aeruginosa, and Clostridium perfringens in a sandy South Florida beach.

The search for alternative indicators of disease-risk from non-enteric pathogens at the beach revealed high densities of targeted bacteria. To explain the high numbers of potential non-enteric pathogens, Staphylococcus aureus and Pseudomonas aeruginosa, in beach sand, we investigated factors affecting their survival and distribution, as well as those of a potential fecal indicator, Clostridium perfringens. Results indicated greater S. aureus and P. aeruginosa survival and proliferation in sterile beach sand, than seawater, with diminished numbers upon exposure to natural micro-predators. C. perfringens remained relatively consistent with initial numbers. Intermediate sand particles (850 µm-2 mm) constituted the major micro-niche; creating implications for beach classification programs. Colonization of sterile sand boxes at the beach by S. aureus and P. aeruginosa confirmed the filtering action (>100×) of beach sand. The use of these potential pathogens in periodic sanitary evaluation of beach sand quality is indicated, regardless of the factors influencing their abundance.

ABC transporters in the CNS - an inventory.

In the present review we provide a summary of ATP-binding cassette (ABC) transporters in the central nervous system (CNS). Our review is focused on transporters of the ABC A, B, C, D, and G families that have been detected in the cells of the neurovascular unit/blood-brain barrier including brain capillary endothelial cells, pericytes, astrocytes, and neurons, as well as in other brain cells, such as microglia, oligodendrocytes, and choroid plexus epithelial cells. In this review, we provide an overview, organized by ABC family, of transporter expression, localization, and function. We summarize recent findings on ABC transporter regulation in the CNS and address the role of ABC transporters in CNS diseases including brain cancer, seizures/epilepsy, and Alzheimer's disease. Finally, we discuss new therapeutic strategies focused on ABC transporters in CNS disease.

Estrogen receptor beta signaling through phosphatase and tensin homolog/phosphoinositide 3-kinase/Akt/glycogen synthase kinase 3 down-regulates blood-brain barrier breast cancer resistance protein.

Breast cancer resistance protein (BCRP) is an ATP-driven efflux pump at the blood-brain barrier that limits central nervous system pharmacotherapy. Our previous studies showed rapid loss of BCRP transport activity in rat brain capillaries exposed to low concentrations of 17-beta-estradiol (E2); this occurred without acute change in BCRP protein expression. Here, we describe a pathway through which sustained, extended exposure to E2 signals down-regulation of BCRP at the blood-brain barrier. Six-hour exposure of isolated rat and mouse brain capillaries to E2 reduced BCRP transport activity and BCRP monomer and dimer expression. Experiments with brain capillaries from estrogen receptor (ER)alpha and ERbeta knockout mice and with ER agonists and antagonists showed that E2 signaled through ERbeta to down-regulate BCRP expression. In rat brain capillaries, E2 increased unphosphorylated, active phosphatase and tensin homolog (PTEN); decreased phosphorylated, active Akt; and increased phosphorylated, active glycogen synthase kinase (GSK)3. Consistent with this, inhibition of phosphoinositide 3-kinase (PI3K) or Akt decreased BCRP activity and protein expression, and inhibition of PTEN or GSK3 reversed the E2 effect on BCRP. Lactacystin, a proteasome inhibitor, abolished E2-mediated BCRP down-regulation, suggesting internalization followed by transporter degradation. Dosing mice with E2 reduced BCRP activity in brain capillaries within 1 h; this reduction persisted for 24 h. BCRP protein expression in brain capillaries was unchanged 1 h after E2 dosing but was substantially reduced 6 and 24 h after dosing. Thus, E2 signals through ERbeta, PTEN/PI3K/Akt/GSK3 to stimulate proteasomal degradation of BCRP. These in vitro and in vivo findings imply that E2-mediated down-regulation of blood-brain barrier BCRP has the potential to increase brain uptake of chemotherapeutics that are BCRP substrates.

Survival potential of Escherichia coli and Enterococci in subtropical beach sand: implications for water quality managers.

Fecal bacteria have traditionally been used as indicator organisms to monitor the quality of recreational waters. Recent work has questioned the robustness of traditional indicators, particularly at seawater bathing beaches. For example, a study of Florida beaches found unexpectedly high abundances of Escherichia coli, fecal coliforms, and enterococci in beach sand. The aim of the present study was to explain these abundances by assessing the survival of E. coli and enterococci in beach sand relative to seawater. We used a combination of quantitative laboratory mesocosm experiments and field observations. Results suggested that E. coli and enterococci exhibited increased survivability and growth in sand relative to seawater. Because fecal bacteria are capable of replicating in sand, at least under controlled laboratory conditions, the results suggest that sand may be an important reservoir of metabolically active fecal organisms. Experiments with "natural" mesocosms (i.e., unsterilized sand or water rich in micropredators and native bacteria) failed to show the same increases in fecal indicators as was found in sterile sand. It is postulated that this was due to predation and competition with indigenous bacteria in these "natural" systems. Nonetheless, high populations of indicators were maintained and recovered from sand over the duration of the experiment as opposed to the die-off noted in water. Indicator bacteria may wash out of sand into shoreline waters during weather and tidal events, thereby decreasing the effectiveness of these indicators as predictors of health risk and complicating the interpretations for water quality managers.

Randomized controlled trial of Siberian ginseng for chronic fatigue.

BACKGROUND: Chronic fatigue greatly affects quality of life and is a common reason for consulting a physician. Since conventional therapy is often of limited help, fatigued patients may use herbal treatments. This randomized controlled trial evaluated the effectiveness of Siberian ginseng. METHOD: Subjects were recruited from advertisements in Iowa (82%) and members of chronic fatigue syndrome support groups (18%). Potential subjects were required to have substantial fatigue > or = 6 months with no identifiable cause. The mean change in a fatigue measure was compared for placebo and Siberian ginseng at 1 and 2 months. Comparisons were for all subjects and for subjects with characteristics previously identified in the literature as important for categorizing chronic fatigue. RESULTS: Ninety-six subjects were randomized to treatment groups, and 76 provided information at 2 months of follow-up. Fatigue among subjects assigned to either placebo or Siberian ginseng was substantially reduced during the study, but differences between treatment groups were not statistically significant in the full sample. Fatigue severity and duration had a statistically significant interaction with response to Siberian ginseng at the P < 0.05 level. Treatment was effective at 2 months for 45 subjects with less severe fatigue (P = 0.04 unadjusted for multiple comparisons) and for 41 subjects with fatigue for > or = 5 years (P = 0.09 unadjusted for multiple comparisons). CONCLUSION: Overall efficacy was not demonstrated. However, the findings of possible efficacy for patients with moderate fatigue suggests that further research may be of value.

Quality of a family medicine preceptorship is significantly associated with matching into family practice.

OBJECTIVES: This study tested whether clinical experiences in family practice are associated with matching into family practice. METHODS: We conducted a prospective cohort study of 913 medical students who completed the Family Practice Preceptorship (FPP) at the University of Iowa from 1990-1996. Using univariate techniques and logistic regression, we compared the background and experiences of those who matched into family practice with those who chose other specialties. RESULTS: Twenty-nine percent (n=267) matched into family practice. Positive independent predictors of family practice match were hometown size less than 10,000 (odds ratio [OR] 1.8), anticipating choosing family practice at matriculation (OR 4.2), and liking to help others (OR 4.1). Negative independent predictors included parental income of at least $120,000 (OR .61), desiring to perform technical procedures (OR .51), and liking the scientific method and research (OR .54). The effect of an early summer clinical experience at a community hospital varied depending on the level of student interest in family practice at matriculation. Students who rated the educational value of the FPP as high or very high were significantly more likely to go into family practice (OR 2.9), even after adjusting for all other student characteristics. CONCLUSIONS: A number of student characteristics and preferences, early clinical experiences, and the perceived quality of a required family medicine preceptorship were significantly and independently associated with students matching into family practice.

Surgeon characteristics associated with mortality and morbidity following carotid endarterectomy.

PURPOSE: To identify surgeon characteristics associated with mortality or morbidity, following carotid endarterectomy (CEA). METHODS: Data on all inpatient discharges from the 284 nonfederal Pennsylvania hospitals were obtained from the Pennsylvania Health Care Cost Containment Council for the period from 1994 to 1995. Physician data were obtained from the Physicians List of the American Medical Association, including name, gender, specialty, year of birth, board certified, and year of licensure. Cases were selected if any of six procedures codes were ICD-9-CM rubric 38.12, indicating CEA. RESULTS: Among the 12,725 cases studied, in-hospital mortality was 0.7%, nonfatal morbidity was 3.0%, and the total bad outcome rate was 3.7%. Surgeons who performed 1 to 2 CEAs over 2 years had the highest mortality (2.0%) and total bad outcome (9.2%) rates. For surgeons performing three or more cases in 2 years, increased volume was not associated with better outcomes. A greater number of years since the surgeon was licensed was associated with greater mortality (p = 0.001), but not with morbidity or bad outcome rates. In regression analyses that adjusted for patient risk, both years since licensure and specialty predicted surgical mortality rate, but only volume predicted surgical bad outcome rate. CONCLUSIONS: More years since licensure and very low patient volume are associated with worse patient outcomes following CEA.

Unexplained symptoms in primary care: perspectives of doctors and patients.

This study evaluated unexplained symptoms in primary care from the perspective of both patients and physicians. The data were obtained from two 1998 statewide surveys, one targeting Medicaid patients and the other all primary care physicians in the state. There were 439 patients who responded (45% response rate) and 280 primary care physicians who responded (33% response rate). Half of the patients and half of the physicians were in non-metropolitan counties. Half of the patients reported unexplained symptom usually or always, and 75% of whom sought help for these symptoms. Fifty-two percent of these patients believed their physician was very concerned about their unexplained symptoms. Eighty percent of them rated their physician as providing the best possible care compared to only 49% of patients whose physician did not care about their unexplained symptoms (P=.001). Among the physicians, only 14% reported very good or excellent satisfaction with managing unexplained symptoms as compared to 44% who claimed similar satisfaction in managing psychological problems. Physicians who saw themselves as more effective in dealing with somatoform symptoms were more likely to be in solo practice (P<.005), or in the same location for at least five years (P=.04). Residence in a nonmetropolitan county did not affect patient reporting of symptoms, patient perception of physician concern about symptoms, or physician satisfaction in managing these symptoms. These results indicate the prevalence and importance of unexplained symptoms in the Medicaid population and the comfort of physicians in managing these symptoms. There is an unmet need among primary care physicians to learn how to manage patients with unexplained symptoms.

Illness fears in the general population.

OBJECTIVES: Because relatively little is known about illness fears, we sought to estimate the prevalence, risk factors, and morbidity associated with such fears in the community. METHODS: We conducted a brief telephone survey of persons aged 40 to 65 years from randomly selected households in the Johnson County, Iowa, area. Respondents were asked whether a series of illness and medical care items made them no more nervous, somewhat more nervous, or much more nervous than other people. Those who reported more discomfort were asked to what extent this interfered with medical care or caused impairment or distress. Information about demographic and health characteristics was also obtained. RESULTS: Five hundred persons, 62% of those contacted, responded to the survey. A factor analysis revealed four fear dimensions: illness/injury, medical care, blood/needle, and aging/death. Five percent of respondents reported much more nervousness in relation to at least four of six illness/injury items, 4% indicated that such fears interfered with their medical care, and 5% reported some negative effect on their life. Similarly, 5% of respondents reported much more nervousness in relation to at least two of four medical care items. Illness/injury fears were somewhat more common in persons with lower income and education and in those with medical conditions. CONCLUSIONS: This survey shows that fears of illness and medical care are common in the general population and indicates that lower socioeconomic status and experience with illness are associated with these fears. The findings also suggest that interference with care occurs among those with the strongest fears.

A comparison of observational studies and randomized, controlled trials.

BACKGROUND: For many years it has been claimed that observational studies find stronger treatment effects than randomized, controlled trials. We compared the results of observational studies with those of randomized, controlled trials. METHODS: We searched the Abridged Index Medicus and Cochrane data bases to identify observational studies reported between 1985 and 1998 that compared two or more treatments or interventions for the same condition. We then searched the Medline and Cochrane data bases to identify all the randomized, controlled trials and observational studies comparing the same treatments for these conditions. For each treatment, the magnitudes of the effects in the various observational studies were combined by the Mantel-Haenszel or weighted analysis-of-variance procedure and then compared with the combined magnitude of the effects in the randomized, controlled trials that evaluated the same treatment. RESULTS: There were 136 reports about 19 diverse treatments, such as calcium-channel-blocker therapy for coronary artery disease, appendectomy, and interventions for subfertility. In most cases, the estimates of the treatment effects from observational studies and randomized, controlled trials were similar. In only 2 of the 19 analyses of treatment effects did the combined magnitude of the effect in observational studies lie outside the 95 percent confidence interval for the combined magnitude in the randomized, controlled trials. CONCLUSIONS: We found little evidence that estimates of treatment effects in observational studies reported after 1984 are either consistently larger than or qualitatively different from those obtained in randomized, controlled trials.

Community characteristics associated with elder abuse.

OBJECTIVES: To help define the relationship between elder abuse rates and counties' demographics, healthcare resources, and social service characteristics. DESIGN: County-level data from Iowa were analyzed to test the association between county characteristics and rates of elder abuse between 1984 and 1993 using univariate correlation analysis and stagewise linear regression. SETTING: Ninety-nine counties in Iowa. PARTICIPANTS: Iowa residents aged 65 years and older. MEASUREMENTS: County-level population-adjusted numbers of abused elderly, abused children, children in poverty, high school dropouts, physicians and other healthcare providers, hospital beds, social workers and caseworkers in the Department of Human Services (DHS). RESULTS: Community characteristics that had a positive association with rates of reported or substantiated elder abuse at the P < .001 level were population density, children in poverty, and reported child abuse. Lower substantiated elder abuse rates were associated at P < .05 with higher community rates of high school dropouts, number of chiropractors, and number of nurse practitioners. After adjusting for number of DHS caseworkers and reported child abuse rates (a surrogate for workload) a district effect persists for substantiated elder abuse cases (P = .002). CONCLUSION: County demographics are risk factors for reported and substantiated elder abuse. The strongest risk factor for reported elder abuse was reported child abuse. The difference in districts may reflect differences in resources and/or differing characteristics of caseworkers who substantiate elder abuse. The risk factors may reflect conditions that influence the amount of elder abuse or the detection of existing elder abuse.

Trends during 25 years of coronary artery bypass operation at St. Luke's Medical Center in Milwaukee, Wisconsin.

BACKGROUND: Most studies of changes in coronary artery bypass graft (CABG) operations are from major academic institutions. The present study evaluated changes in CABG operations since 1968 in a community hospital. METHODS: The data were from the St. Luke's Medical Center Cardiovascular Data Registry in Milwaukee, Wisconsin. Mortality rates, risk factors, overall patient risk, and surgical procedures were compared from 1968 to 1994. RESULTS: There was a dramatic decrease in 30-day mortality rates from 1968 to 1972. After 1976, mortality rates increased because of higher risk patients, but the mortality rate, adjusted for patient risk, continued to decline. Both internal mammary arteries and sequential grafts were widely used by 1972, followed by a decline in use until 1980, and then a steep increase in use from 1980 to the present. CONCLUSIONS: This study provided evidence from a community hospital that the skills of the surgical teams improved first dramatically then gradually. The pattern of adapting new surgical techniques suggested that these techniques were critically evaluated for several years after they were introduced.

Prognostic factors for persons with idiopathic chronic fatigue.

BACKGROUND: The simultaneous examination of a large number of patient characteristics in a prospective study of patients with chronic fatigue. OBJECTIVE: To compare the relative importance of these characteristics as prognostic factors. METHODS: The data analyzed were from 199 subjects in a registry of persons who were aged 18 years or older and had idiopathic fatigue for at least 6 months. All subjects completed an extensive baseline questionnaire that provided information about fatigue, demographic characteristics, medical conditions, lifestyle, sleeping habits, psychological characteristics, and the presence of criteria for chronic fatigue syndrome. Changes in fatigue severity from baseline to 2-year follow-up were tested for an association with risk factors at baseline and with changes in symptoms other than fatigue during the follow-up period. RESULTS: The following characteristics at baseline significantly and independently predicted greater fatigue improvement: less unclear thinking, fewer somatoform symptoms not used to define chronic fatigue syndrome, infrequent awakening, fewer hours sleeping, and being married. Of 29 subjects who at baseline reported no somatoform symptoms unrelated to chronic fatigue syndrome and who thought clearly most of the time, 8 substantially improved, compared with 1 of 29 subjects who had more than 2 somatoform symptoms and never thought clearly (P = .01). Improvements in the following symptoms were significantly and independently associated with improvements in fatigue: unclear thinking, depression, muscle aches, and trouble falling asleep. CONCLUSIONS: This study identified characteristics of subjects that seem to be of prognostic importance for idiopathic chronic fatigue. Symptoms that change concomitantly with changes in fatigue may be intrinsically linked to fatigue.

Prestige of training programs and experience of bypass surgeons as factors in adjusted patient mortality rates.

OBJECTIVES: The relation of physician performance to physician training and experience is not well understood. The aim of this study was to examine whether indicators of physician background and experience were associated with an objective measure of physician performance. METHODS: Physician background information obtained from the Directory of Board-Certified Medical Specialists was linked to physician risk-adjusted mortality rates obtained from three statewide data bases of coronary artery bypass surgeons. Subjects were 275 surgeons who performed CABG surgery on 83,547 patients during the years 1989 to 1992. Surgical performance was measured by the mortality ratio (MR), the ratio of the observed to the predicted patient mortality rate as determined by detailed clinical information. Training institutions and physicians were characterized as prestigious if they were listed as outstanding in published articles. RESULTS: Surgical performance was not associated with graduation from an American medical school; attendance at a prestigious medical school, residency, or fellowship program; or an academic appointment. Mortality ratios decreased with increased volume and increased with years of experience, age, and academic rank. Surgeons were more likely to be considered a "best doctor" if they had more years experience and trained at a prestigious residency or fellowship program. CONCLUSIONS: Training at a prestigious institution was associated with identification as a "best" doctor but not with lower mortality ratios.

Pre-transplant identification of risk factors that adversely affect length of stay and charges for renal transplantation.

BACKGROUND: In the current era of renal transplantation, increasing attention is being focused on resource utilization. The purpose of this study was to identify demographic, medical and immunologic risk factors that are associated with changes in length of stay (LOS) and charges for renal transplantation. METHOD: The study was a retrospective analysis of 311 consecutive renal transplants performed at a single institution. Univariate and multivariate analyses were used to examine relationships between risk factors, LOS, charges and post-operative complications. RESULTS: The following pre-transplant variables were found to be independently significant in predicting increased LOS and/or charges: African-American race, obesity for women, chronic obstructive pulmonary disease (COPD), presence of cardiac disease or previous stroke, pre-transplant dialysis time > or = 1 yr, a 10% increase in panel reactive antibody (PRA), cadaver donor and retransplantation. The analyses were performed with and without adjustment for key outcome variables such as delayed graft function (DGF) and use of induction antibody therapy. Increased LOS or charges for specific risk factors could be attributed to increased complication rates, including delayed graft function seen with various co-morbidities, or increased immunologic risk and more frequent use of induction antibody therapy. CONCLUSION: Analysis of linked financial and clinical databases can reveal demographic, medical and immunologic risk factors that correlate with LOS, charges and complications for renal transplantation. Efforts to establish quantitative relationships for various risk factors relative to resource utilization will become important in managed care and/or capitated healthcare delivery systems.

What clinical information resources are available in family physicians' offices?

BACKGROUND: When faced with questions about patient care, family physicians usually turn to books in their personal libraries for the answers. The resources in these libraries have not been adequately characterized. METHODS: We recorded the titles of all medical books in the personal libraries of 103 randomly selected family physicians in eastern Iowa. We also noted all clinical information that was posted on walls, bulletin boards, refrigerators, and so forth. Participants were asked to describe their use of other resources such as computers, MEDLINE, reprint files, and "peripheral brains" (personal notebooks of clinical information). For each physician, we recorded how often the resources were used to answer clinical questions during 2 half-day observation periods. RESULTS: The 103 participants owned a total of 5794 medical books, with 2836 different titles. Each physician kept an average of 56 books in the office. Prescribing references (especially the Physicians' Desk Reference) were most common (owned by 100% of the participants), followed by books on general internal medicine (99%), adult infectious disease (89%), and general pediatrics (83%). Books used to answer clinical questions were more likely to be up to date (copyright date within 5 years) than unused books (74% vs 27%, P <.001). Items posted on walls included drug dosage charts and pediatric immunization schedules. Only 26% of the physicians had computers in their offices. CONCLUSIONS: Drug-prescribing textbooks were the most common type of book in family physicians' offices, followed by books on general internal medicine and adult infectious diseases. Although many books were relatively old, those used to answer clinical questions were generally current.

Is paracervical block safe and effective? A prospective study of its association with neonatal umbilical artery pH values.

BACKGROUND: Paracervical blocks (PCBs) relieve labor pain, but reports of associated complications have caused many physicians to question their safety. METHODS: We designed a prospective observational study to examine the association between PCBs and umbilical artery hydrogen ion concentration (pH) values. A total of 261 healthy women in labor were recruited from a community hospital. Physicians used 1% lidocaine for the PCBs. We used multivariate linear regression to model predictors of umbilical artery pH at birth. RESULTS: Of the women studied, 238 (91%) received analgesia during labor (nalbuphine, PCB, pudendal, caudal, or epidural). Of these, 126 (48%) received at least one PCB (191 were given), and 197 (76%) received at least one dose of nalbuphine (237 were given). Univariate analyses showed no significant differences in mean 1-minute Apgar scores, 5-minute Apgar scores, umbilical artery pH, resuscitation with oxygen by mask, or length of newborn stay according to either PCB or nalbuphine exposure. Factors significantly associated with lower umbilical artery pH in a linear regression analysis included longer second stage of labor (-0.032 pH units for each 1-hour increase; 95% confidence interval [CI], -.046 to -.018), pudendal block (-0.022; 95% CI, -.040 to -.004), intrauterine pressure catheter use (-0.029; 95% CI, -0.053 to -.006), nuchal cord (-0.027; 95% CI, -.051 to -.004), and midforceps delivery (-0.080; 95% CI, -.159 to .000). Increasing maternal age and induction with either artificial rupture of membranes or gel were associated with higher umbilical artery pH values. CONCLUSIONS: After adjusting for other variables, neither PCB nor nalbuphine use were associated with umbilical artery pH at birth. PCBs using 1% lidocaine injected superficially should be considered a safe and effective form of obstetric analgesia. PCBs may be especially useful for women giving birth in hospitals where other obstetric anesthesia services are not readily available.