Modern theory of tuberculosis: culturomic analysis of its historical origin in Europe and North America.

INTRODUCTION: An historical account of the modern theory of tuberculosis (TB) using a culturomic analysis has not been studied. OBJECTIVE: To analyze, using culturomic methods, the history of our modern understanding of TB as a unitary disease. METHODS: A culturomic analysis of millions of digitized texts was undertaken to quantify 200-year trends in usage of the modern term tuberculosis and pre-modern terms consumptive, phthisis, and scrofula, and to correlate these trends with significant historical events. RESULTS: Our understanding of TB originated with Laënnec in Paris, who proposed that the seemingly disparate wasting conditions phthisis, scrofula, and consumption were each related to the same post-mortem anatomical sign: the tubercle. The term tuberculosis was coined by Schonlein in 1829, but the term's usage remained uncommon until Villemin's 1865 discovery that TB was a communicable disease, Koch's 1882 discovery of Mycobacterium tuberculosis, and Pasteur's 1884 discovery of a vaccine against another communicable disease, smallpox. CONCLUSION: Our modern understanding of TB as a unitary disease was embraced slowly. Acceptance required new terminology describing the idea, scientific confirmation that TB is an infectious disease, and evidence suggesting that it might be prevented. An innovative idea is not enough to induce widespread acceptance. The study illustrates how culturomic methods can be used to study the adoption and diffusion of an innovation, in this case the modern theory of TB.

Early prediction of cardiac allograft vasculopathy and heart transplant failure.

Early risk-prediction is essential to prevent cardiac allograft vasculopathy (CAV) and graft failure in heart transplant patients. We developed multivariate models to identify patients likely to experience CAV, severe CAV, and failure due to CAV, at 1, 5 and 10 years. A cohort of 172 patients was followed prospectively for 6.7 ± 3.9 years. Logistic regression models were developed and cross-validated using bootstrap resampling. Predictive markers of atherothrombosis (myocardial fibrin deposition, and loss of vascular antithrombin and tissue plasminogen activator) and arterial endothelial activation (intercellular adhesion molecule-1 expression) were measured in serial biopsies obtained within 3 months posttransplant. Most markers were univariately associated with outcome. Multivariate models showed that loss of tissue plasminogen activator was the dominant and, in most cases, only predictor of long-term CAV (p < 0.001), severe CAV (p < 0.001), and graft failure due to CAV (p < 0.001). The models discriminated patients having adverse outcomes, had particularly high negative predictive values (graft failure due to CAV: 99%, 99% and 95% at 1, 5 and 10 years) and predicted event incidence and time to event. Early absence of atherothrombotic risk identifies a patient subgroup that rarely develops CAV or graft failure, implying that this low-risk subgroup could possibly be followed with fewer invasive procedures.

Lower pole I: a prospective randomized trial of extracorporeal shock wave lithotripsy and percutaneous nephrostolithotomy for lower pole nephrolithiasis-initial results.

PURPOSE: The efficacy of shock wave lithotripsy and percutaneous stone removal for the treatment of symptomatic lower pole renal calculi was determined. MATERIALS AND METHODS: A prospective randomized, multicenter clinical trial was performed comparing shock wave lithotripsy and percutaneous stone removal for symptomatic lower pole only renal calculi 30 mm. or less. RESULTS: Of 128 patients enrolled in the study 60 with a mean stone size of 14.43 mm. were randomized to percutaneous stone removal (58 treated, 2 awaiting treatment) and 68 with a mean stone size of 14.03 mm. were randomized to shock wave lithotripsy (64 treated, 4 awaiting treatment). Followup at 3 months was available for 88% of treated patients. The 3-month postoperative stone-free rates overall were 95% for percutaneous removal versus 37% lithotripsy (p <0.001). Shock wave lithotripsy results varied inversely with stone burden while percutaneous stone-free rates were independent of stone burden. Stone clearance from the lower pole following shock wave lithotripsy was particularly problematic for calculi greater than 10 mm. in diameter with only 7 of 33 (21%) patients becoming stone-free. Re-treatment was necessary in 10 (16%) lithotripsy and 5 (9%) percutaneous cases. There were 9 treatment failures in the lithotripsy group and none in the percutaneous group. Ancillary treatment was necessary in 13% of lithotripsy and 2% percutaneous cases. Morbidity was low overall and did not differ significantly between the groups (percutaneous stone removal 22%, shock wave lithotripsy 11%, p =0.087). In the shock wave lithotripsy group there was no difference in lower pole anatomical measurements between kidneys in which complete stone clearance did or did not occur. CONCLUSIONS: Stone clearance from the lower pole following shock wave lithotripsy is poor, especially for stones greater than 10 mm. in diameter. Calculi greater than 10 mm. in diameter are better managed initially with percutaneous removal due to its high degree of efficacy and acceptably low morbidity.

A critical birth weight and other determinants of survival for infants with severe intrauterine growth restriction.

Our objective was to assess the perinatal management and neonatal outcomes of premature, severely intrauterine growth-restricted (IUGR) neonates. A cohort of neonates <1000 grams, < or = first percentile for weight, and <37 weeks' gestation was identified and matched 2:1 to two control sets of premature, appropriate-for-gestational age (AGA) infants-one with similar gestational age (AGA-GA group) and the other with similar birth weight (AGA-BW group) to determine the effect of IUGR on the outcome of the premature infant. The IUGR group was then examined in detail for descriptive statistics. Data were analyzed by t-tests and Chi-square analyses where appropriate. The IUGR infants had worse outcomes than AGA-GA controls but had somewhat better results than the AGA-BW controls. In the IUGR group, a birth weight less than 550 grams was significantly associated with neonatal death (p < 0.001). However, increasing gestational age was not associated with neonatal survival (p = 0.661) if birthweight remained below 550 grams. Classical cesarean delivery was associated with neonatal death (p = 0.003). Neonatal variables associated with poor outcome included patent ductus arteriosus (p = 0.034), feeding intolerance (p = 0.046), and failure to thrive (p = 0.05). Overall, neonatal survival was 73%. Of the surviving neonates, 69% had evidence of neurodevelopmental delay when tested at 6 and 12 months. Premature, growth-restricted neonates with birth weights of <550 grams versus those of >550 grams have dismal outcomes despite a gestational age that is compatible with survival.

Vitamins C and E: missing links in preventing preterm premature rupture of membranes?

We propose that generation of reactive oxygen species may be a potentially reversible pathophysiologic pathway leading to preterm premature rupture of the membranes. Reactive oxygen species generated by the body's response to diverse insults such as infection, cigarette smoking, bleeding, or cocaine use can activate collagenolytic enzymes and impair fetal membrane integrity. Vitamin E, a lipid-soluble antioxidant, inhibits membrane-damaging effects of reactive oxygen species-induced lipid peroxidation. Vitamin C, a water-soluble antioxidant in plasma, stimulates and protects collagen synthesis while recycling vitamin E. Prior evidence shows that (1) damage by reactive oxygen species can impair fetal membrane integrity, (2) reduced midgestation levels of vitamin C are associated with preterm premature rupture of membranes, and (3) these vitamins can be safely and effectively absorbed and delivered to gestational tissues. Current prenatal vitamin preparations contain vitamins C and E in concentrations that are less than 1/3 and 1/10, respectively; these levels have been suggested for effective antioxidant protection. We hypothesize that increased dietary consumption or supplementation of vitamins C and E during pregnancy may reduce physiologically the risks of that portion of preterm premature rupture of membranes that is mediated by excessive or undamped peroxidation of fetal membranes. This hypothesis, if confirmed, should stimulate initiation of therapeutic trials to test the efficacy of enhanced supplementation with vitamins C and E during pregnancy to prevent preterm premature rupture of membranes.

Reactive oxygen species and preterm premature rupture of membranes-a review.

Preterm premature rupture of membranes (PPROM) results initially from damage to collagen in the chorioamnion leading to a tear in the membrane. Tissue-damaging molecules called reactive oxygen species (ROS) are capable of damaging collagen in the chorioamnion that could lead to PPROM. This hypothesis is supported by epidemiological studies linking clinical conditions known to produce ROS or reduce antioxidant protection to PPROM, by in-vitro studies in which membrane segments exposed to ROS exhibited tissue alterations consistent with PPROM, and by clinical studies showing that chorioamnion and amniotic fluid samples obtained from PPROM patients exhibit excessive collagen degradation. The role of antioxidants to protect the chorioamnion from ROS damage has been demonstrated in one in-vitro study. A prospective, randomized blinded trial of antioxidant therapy during pregnancy is needed to evaluate this approach for the prevention of PPROM.

Pretreatment of human amnion-chorion with vitamins C and E prevents hypochlorous acid-induced damage.

OBJECTIVE: Preterm premature rupture of fetal membranes has been associated with infection, cigarette smoking, and bleeding. Hypochlorous acid (a reactive oxygen species) is central to the body's response to infection, yet it may damage surrounding tissue while destroying pathogens. We examined in vitro the tissue-damaging actions of hypochlorous acid on the amnion-chorion and the protective role provided by pretreatment with vitamins C and E. STUDY DESIGN: Amnion-chorion samples were obtained from 4 term pregnancies, cut into segments, and divided into 6 exposure groups. Half were treated in advance with vitamins C and E (Trolox C) and half were treated with buffer solution alone. After rinsing, amnion-chorion samples were exposed to hypochlorous acid at 1 or 10 mmol/L for 4 hours. Histologic and immunocytochemical evaluations were conducted with antibodies for collagen I and IV. RESULTS: Extensive damage to amniotic epithelium and collagen I but not collagen IV resulted from hypochlorous acid exposure and was dose related. Pretreatment with vitamins C and E prevented this damage in all cases. CONCLUSION: Hypochlorous acid damages the amniotic epithelium and collagen I in the amnion-chorion. The protection against hypochlorous acid-induced damage provided by antioxidant therapy (vitamins C and E) is of therapeutic significance.

Maternal and transplacental effects of cocaine.

Pregnancy is a dynamic process, and maternal as well as fetal risks from cocaine use in pregnancy may differ as pregnancy progresses. Three areas of biology offer opportunities for reevaluating cocaine's effects in pregnancy: (1) Maternal cardiovascular and neurologic responses to cocaine hydrochloride are enhanced when compared with responses in nonpregnant subjects to the same dose per kilogram or to metabolites of crack cocaine. (2) During first trimester placental implantation, oxygen availability to the fetus may normally be limited. Cocaine-induced uterine artery vasoconstriction may lead to reperfusion and oxygen toxicity to the fetus from released reactive oxygen species. (3) Cocaine transport in the first and early second trimester may, in part, be across the placental chorion-amnion. Lacking a skin barrier, the fetus at mid-pregnancy may come in direct contact with high concentrations of cocaine in amniotic fluid, a reservoir that clears cocaine slowly, thereby prolonging exposure during critical periods of fetal neurotransmitter formation. Exploring these three areas of biology may offer new approaches to understanding the ultimate impact of prenatal cocaine exposure on maternal and fetal biology.

Cocaine in pregnancy. Recent data on maternal and fetal risks.

Cocaine continues to be abused during pregnancy, creating increased demands on the health care system. Epidemiology and basic science research have identified and confirmed risks of adverse maternal and fetal effects when cocaine is used during pregnancy. These effects of cocaine in pregnant women often are influenced by a number of confounding variables. This article reviews those cocaine effects as well as recent data, which examine in greater detail the risks of adverse outcomes of prenatal cocaine exposure during pregnancy.

An introduction to reactive oxygen species and their possible roles in substance abuse.

There is a growing body of information relating diverse diseases and the consequences of injury to generation and toxicity of reactive oxygen species (ROS). Recently, it has been shown that the fetus and its membranes are also vulnerable to this toxicity, suggesting that a number of obstetric diseases may result from exposure to ROS, which are ubiquitous in aerobic organisms. Endogenous antioxidants, including superoxide dismutase, catalase, and glutathione peroxidase are essential for defense against ROS. It is significant that all antioxidants appear to be down-regulated in the fetus and membranes, suggesting the possibility that any process that further depresses their activities or increases the burden of ROS may compromise fetal development or maternal health. When permitted to accumulate, ROS can damage all classes of macromolecules, including lipids, proteins, and nucleic acids. Toxicity includes mutation, protein degradation, and lipid peroxidation, which can severely disturb membrane permeability and alter intracellular calcium and pH. An understanding of the generation and toxicity of ROS should help to define their potential roles in obstetric disease and lead to innovative preventive and therapeutic approaches.

Adverse consequences of prenatal illicit drug exposure.

Our appreciation of the impact on health of illicit drug use is growing. Once considered a maternal risk, prenatal drug exposure may target fetal neurobehavior, affecting attention and learning as the child grows into adulthood. Cocaine, opiates, marijuana, and amphetamines have each been scrutinized for adverse actions on placental transport, fetal behavior states, newborn withdrawal, and childhood learning and attentive skills. Neurotransmitter analysis in the animal model after prenatal drug exposure now provides biological support for these clinical findings. The increasing prevalence of drug use by pregnant women, the effect of illicit drug use on transmission of the human immunodeficiency virus, and the maternal and fetal consequences of illicit drug exposure make illicit drug use in pregnancy a central challenge in maternal-fetal medicine and a need-to-know field in general obstetrics.

Doppler velocimetry of intraplacental fetal vessels in the second trimester: improving the prediction of pregnancy complications in high-risk patients.

The purpose of our study was to assess the value of fetal intraplacental velocimetry in predicting adverse pregnancy outcome in high-risk patients. Thirty-two women with pregnancies of 22 to 25 weeks' gestation were evaluated. They had demonstrated abnormal first-trimester Doppler characteristics, yet had normal second-trimester umbilical artery velocimetry. Doppler waveforms were obtained and the ratio between intraplacental and umbilical artery resistance indices was calculated. Abnormally high ratios of intraplacental to umbilical artery resistance indices were associated with a significantly higher incidence of pregnancy complications. Among women with abnormal ratios, 17 (80%) of 21 pregnancies had later complications, whereas among those with normal ratios, only two (18%) of 11 women experienced later complications. This study demonstrates that analysis of the ratio between intraplacental and umbilical artery resistance indices in the second trimester improves the diagnostic value of Doppler velocimetry in pregnancies at risk for later obstetric complications.

Pension benefits among the aged: conflicting measures, unequal distributions.

Estimates of total benefits paid by employer sponsored pension plans seem to vary widely between different data sources and measures. Such discrepancies have been used to support differing conclusions about the effectiveness of the pension system. This article examines several measures of aggregate pension benefits in 1990, a year particularly rich in available data. Exploratory analysis suggests that the greatest source of discrepancy lies in differing treatments of lump-sum distributions, although the study also identifies several other types of payments that are variously, and erroneously, counted as pension income. Age of recipients is an important factor in analyzing different measures of aggregate pension benefits; discrepancies are much smaller among the aged than in the population as a whole. The analysis also provides new evidence about the unequal distribution of pension benefits among the aged, confirming from two data sources that benefits are heavily concentrated among higher income groups.

Does progesterone potentiate the in vitro effect of cocaine on papillary myocardium in Long-Evans rats?

Cocaine's cardiotoxicity was reported in our laboratory to be augmented by progesterone. This study was designed to replicate these findings and determine the mechanism. Rats were pretreated with progesterone (study) or vehicle (control). Papillary muscles were attached to transducers in Krebs' baths. Paced contractility parameters were measured while increasing concentrations of cocaine, norepinephrine, or tetrodotoxin were added. In nine baths, yohimbine was added before the cocaine. Twelve rats were pretreated with reserpine, and cocaine added to the baths. In muscles from nonreserpinized control rats, there was a small positive inotropic effect (8.6% above baseline) at 10(-6) M cocaine, not seen in study muscles. There were no differences between study and control muscles in cocaine concentrations at which muscles became acontractile, nor in responses to norepinephrine, tetrodotoxin, or to cocaine after the addition of yohimbine or following reserpine pretreatment. We could not replicate cocaine's previously reported increased negative inotropic effect in progesterone-treated rats, nor was there evidence supporting possible mechanisms for this reported effect.

The use of a break-even analysis: financial analysis of a fast-track program.

OBJECTIVE: To calculate the financial break-even point and illustrate how changes in third-party reimbursement and eligibility could affect a program's fiscal standing. METHODS: Demographic, clinical, and financial data were collected retrospectively for 446 patients treated in a fast-track program during June 1993. The fast-track program is located within the confines of the emergency medicine and trauma center at a 1,050-bed tertiary care Midwestern teaching hospital and provides urgent treatment to minimally ill patients. A financial break-even analysis was performed to determine the point where the program generated enough revenue to cover its total variable and fixed costs, both direct and indirect. RESULTS: Given the relatively low average collection rate (62%) and high percentage of uninsured patients (31%), the analysis showed that the program's revenues covered its direct costs but not all of the indirect costs. CONCLUSIONS: Examining collection rates or payer class mix without examining both costs and revenues may lead to an erroneous conclusion about a program's fiscal viability. Sensitivity analysis also shows that relatively small changes in third-party coverage or eligibility (income) requirements can have a large impact on the program's financial solvency and break-even volumes.

Community hospital and medical school cooperation in continuing medical education.

PURPOSE: To determine the extent and trends of cooperation in continuing medical education (CME) between community teaching hospitals and medical schools in the United States. METHOD: A questionnaire was sent in September 1992 to the directors of CME at 276 teaching hospital members of the Association for Hospital Medical Education (AHME). The survey was designed to answer two questions: (1) What is the extent of cooperation between hospital CME providers and medical schools? (2) In the next three years will community hospitals seek competitive or collaborative relationships in CME with medical schools? RESULTS: By late April 1993, 216 (78%) of the questionnaires had been returned. Of these, 177 (64% of the sample) were analyzed. Of the responding hospitals, 91 (52%) cooperated with 92 medical schools in CME; 75 (45%) of the hospitals planned to increase cooperation. Only ten (11%) of the hospitals described their current CME relationship with a medical school as "competitive in most areas"; 23 (14%) expected to increase competition in the next three years. Forty-one (24%) of the respondents were part of a community hospital CME consortium; only 20 (16%) of the other institutions expected to participate in a consortium in the next three years. Hospital size and membership in the Association of American Medical Colleges' Council of Teaching Hospitals were generally correlated with current and future competition in CME with a medical school and likely participation in a community CME consortium. CONCLUSION: The majority of teaching hospital members of the AHME perceived that they would have cooperative relationships in CME with affiliated medical schools in the three years following the survey. These collaborative relationships should provide an important basis for the further planning and development of medical education consortia.

Lack of mandibular movement manifested by absent fetal swallowing: a possible factor in the pathogenesis of micrognathia.

This study was performed to assess the association of lack of mandibular movement as manifested by absent fetal swallowing and micrognathia in a nonrestrictive intrauterine environment. Over a 5-year period, 14 fetuses with sonographic findings of polyhydramnios (amniotic fluid index [AFI] more than 20 cm), absent mandibular movement, and a nonvisualized fetal stomach, all consistent with absent fetal swallowing, were followed. A group of 14 fetuses, each with polyhydramnios (AFI more than 20 cm), yet with sonographic detection of fetal swallowing, served as controls. All gravidas in both groups were normoglycemic throughout gestation. Subsequent mandibular development was assessed at delivery or autopsy. Analysis of the data revealed that in the study group, 12 of these infants were liveborn, and two were stillborn. Eleven of the liveborn infants had an early neonatal death. All 14 infants of the study group demonstrated micrognathia. None of the control infants (all of whom survived) had micrognathia. In conclusion, this study supports the concept that normal mandibular growth may depend on the presence of mandibular movement during intrauterine development.

Clinical management of drug dependency in pregnancy.

In summary, the pregnant substance abuser challenges formal coordination between community-based programs in obstetrics, pediatrics, drug and alcohol treatment, and mental health. Moreover, since substance abuse often is a manifestation of a dysfunctional lifestyle, medical treatment must be linked to education and ultimately, career planning. Some wish that the problem would just go away. Others may feel that the problem is too enormous or too vague for solutions. Neither of these attitudes is appropriate. Identifying and mobilizing the pregnant substance abuser into health care is truly a window of opportunity. Successful rehabilitation into a drug-free lifestyle for the woman and her baby is the reward for this effort.