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.

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.

Comparison of the effects of pindolol and atenolol on hemodynamic function in systemic hypertension.

A randomized double-blind study was performed on a group of mild hypertensive patients (WHO class I) to compare the hemodynamic effects of pindolol and atenolol. Blood pressure (BP) was monitored with a mercury gauge sphygmomanometer, while cardiac function and peripheral arterial flows were measured by the noninvasive technique of bioelectric impedance. After a 2-week washout period, patients with a diastolic BP greater than 95 mm Hg but less than 114 mm Hg were randomized into the pindolol (29 patients) or atenolol (28) treatment groups. Patients were treated with 1 of the 2 drugs in an incremental fashion for 12 weeks. Cardiovascular function was measured after the washout period and at the end of the 12-week treatment period. Baseline hemodynamics were similar in both groups. The 2 drugs were equally effective in lowering both systolic and diastolic BP. Hemodynamically, pindolol lowered BP by decreasing total peripheral resistance (-406 +/- 145 dynes.s.cm-5) while atenolol decreased cardiac index (-0.2 +/- 0.1 liters/min/m2) associated with a decrease in heart rate (-12 +/- 2 beats/min). Regarding peripheral vascular beds, pindolol lowered arm vascular resistance (-198 +/- 72 mm Hg/liter/min) and leg vascular resistance (-73 +/- 25 mm Hg/liter/min), especially when subjects who did not respond to pindolol were excluded from the analysis. Both arm (5.5 +/- 5.4% increase above baseline) and leg (1.2 +/- 4.4% increase above baseline) arterial flow indexes were maintained with pindolol. Conversely, atenolol decreased the arm arterial flow index (-9,8 +/- 5.6% decrease below baseline), but not significantly and with no change in resistance (+54 +/- 62 mm Hg/liter/min).(ABSTRACT TRUNCATED AT 250 WORDS)

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.

The value of age and severity as predictors of costs in geriatric head trauma patients.

The costs of inpatient hospital care for treating head trauma were examined in 125 patients over the age of 50. Regression analysis indicated that injury severity, as measured by the admitting Glasgow Coma Scale, was a good predictor of hospital cost, while patient age was unrelated to cost. The regression relationship, however, was quadratic (not linear), indicating that least injured and severely injured patients cost less than moderately injured patients. These findings are in direct contrast with the commonly held belief that the elderly consume more hospital resources than younger patients. They suggest the need for a reexamination of the use of age in setting prospective reimbursement amounts in certain diagnoses, and in making resource allocation decisions relative to geriatric programming at the hospital level. Head trauma patients are costly because they are sick, not because they are old.

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.

Prenatal cocaine exposure to the fetus: a sheep model for cardiovascular evaluation.

Transplacental passage of cocaine in response to maternal administration of intravenous (IV) cocaine in doses of 1.0 and 2.0 mg/kg was studied in 6 pregnant ewes and fetuses and correlated with maximum changes in maternal and fetal blood pressures (BP), heart rates (HR) and fetal arterial blood gas values. Certain animals were given larger doses (3.0 and 5.0 mg/kg) of cocaine to examine cocaine-related cardiopulmonary and neurologic sequelae. Cocaine was extracted on C-18 sorbent columns and analyzed by gas chromatography. At 1.0 and 2.0 mg/kg, cocaine produced dose-dependent increases in maternal HR and BP which were maximum by 1 minute. The fetal response was characterized by maximum increases in BP and decreases in PO2 by 3 minutes and increases in HR by 15 minutes. Cocaine rapidly appeared in the fetal circulation, was approximately 15% of maternal concentrations by 5 minutes, and was undetectable in both circulations by 60 minutes. At cocaine doses of 3.0 and 5.0 mg/kg significant maternal cardiopulmonary and neurologic complications were encountered including bradyarrhythmias, respiratory distress, seizure and death. These data indicate that cocaine exerts direct drug actions upon maternal cardiovascular and neurologic function. In addition, cocaine affects fetal cardiovascular function directly via transplacental passage and indirectly by fetal hypoxemia from cocaine-induced uterine artery vasoconstriction. (NIDA 04415)

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.

Effects of low-birth-weight breech delivery on neonatal mortality.

The influence of breech presentation on neonatal mortality was studied in 77 viable low-birth-weight breech deliveries. Neonates were divided into 3 weight groups: 1000-1499 g, 1500-1999 g, and 2000-2499 g. The antepartum and intrapartum characteristics of the 3 weight groups were detailed. The 17 neonates who died were studied to determine if alternative delivery methods would have prevented their deaths. Survival rates were 45% in the 1000-1499-g group, 76% in the 1500-1999-g group, and 97% in the 2000-2499-g group. Cervical head entrapment and fetal bradycardia were ominous intrapartum complications, but severe prematurity with respiratory distress syndrome and fetal hydrops were the primary causes of neonatal death. From these data, it is concluded that 1) intrapartum management and delivery of the low-birth-weight breech presentation infant should be individualized, and 2) cesarean section for routine delivery is not justified.

Cell surface lipid in the amniotic fluid.

Limitations of cell staining and light microscopy have led to confusion as to the etiology and morphologic characteristics of nile-blue-sulfate-stained orange cells in amniotic fluid. Nomarski Differential Interference Contrast Microscopy (NDICM) was used to study these cells as they appear in their unstained state. The presence of lipid-bearing cells was correlated with gestational age and mode of delivery, and incubation studies were applied toward an evaluation of the mechanism of lipid formation. Lipid-bearing cells in the amniotic fluid appeared after 37 1/2 weeks' gestation in association with fetal lung maturity.

Acute transient thrombocytopenia associated with cocaine abuse in pregnancy.

A case is described of cocaine-induced severe transient thrombocytopenia associated with a hypertensive crisis at 21 weeks' gestation. Liver function tests and coagulation studies were all within normal ranges. Blood pressure was controlled with hydralazine. This clinical presentation, similar to severe preeclampsia, should be considered in the differential diagnosis of acute hypertension and low platelet count, especially in early gestations when preeclampsia is relatively rare. Unlike severe preeclampsia, for which active intervention and delivery are usually selected, cocaine-related hypertension-thrombocytopenia, especially in very premature gestations, may warrant conservative management.

Fetal and neonatal cardiopulmonary response to histamine.

Effects of intravenous histamine and its H1 receptor blocker (Benadryl) were investigated in near-term fetal and in newborn lambs. Fetuses were studied before and after closure of the ductus arteriosus. Newborn lambs were chronically instrumented and the same animal was tested periodically from 3 to 70 days old. The results show that a) in the fetus whose pulmonary vascular resistance is already high, histamine produces a profound pulmonary vasodilation; b) in contrast, in the neonate with reduced pulmonary vascular resistance, histamine produces pulmonary vasoconstriction similar to that of the adult; c) both responses can be attenuated by Benadryl indicating that they are mediated by the same receptor; d) in the fetus, histamine produces marked constriction of the ductus arteriosus which could be partly attributed to the pulmonary vasocilatation; and e) when neonatal pulmonary vascular resistance was raised by hypoxia, histamine elicited a biphasic response, part of which was blocked by Benadryl. These findings are discussed in terms of their possible role in cardiovascular and pulmonary changes that occur after birth.

Water vacuum suction curettage (WVSC): one year's experience.

PIP: At Tripler Army Medical Center in Honolulu abortion patients underwent suction curettage using either an electric pump unit (21, group A) or a simple water vacuum pump (WVSC) (28, group B). In both groups the use of the flexible 6 mm uterine curette and method of curettage were the same. For groups A and B the average blood losses were 40 ml and 39 ml. Average tissue volumes removed were 26 ml and 39 ml (greater yield reflects more patients at gestation of 9-10 weeks). From September 1971 to August 1972 400 patients of gestation of 10 weeks or less were curettaged using WVSC. Most of the operations were performed by first-year residents. Complications requiring readmission were not skewed towards largest gestations but distributed throughout the groups suggesting importance of individual technique in equipment use. The complications included retained products of conception (6), endometritis (2), endometritis with retained products of conception (3), and hermorrhage (1). Advantages of the WVSC unit are 1) quiet sound of running water rather than harsh sound of electric pump, 2) requirement of only a standard waterhead making method available to impoverished areas where electricity may be precious, 3) failsafe, unidirectional suction, 4) easy storage, transport, and assemblage, and 5) lack of need for safety pop-off valve because of intrinsic lag time from close of system to development of maximum suction. With its simplicity, safety, and flexibility WVSC is best suited for outpatients.^ieng

Effect of alpha 1 receptor blockade upon maternal and fetal cardiovascular responses to cocaine.

Previous studies in pregnant ewes have demonstrated that intravenous (IV) cocaine produces increased maternal blood pressure and vasoconstriction of the uterine arteries, resulting in decreased uterine blood flow and decreased fetal oxygen levels. To determine whether these responses to cocaine were mediated by alpha 1-adrenergic receptor stimulation, cocaine was administered to four pregnant ewes before and after phenoxybenzamine hydrochloride, an alpha 1 receptor antagonist. Before phenoxybenzamine infusion, cocaine 2.0 mg/kg produced a 53% increase in maternal mean arterial pressure (MAP), a 50% reduction in total uterine blood flow, and a 191% increase in uterine vascular resistance. Cocaine also increased fetal MAP by 24%, increased the fetal heart rate (FHR) by 51%, and reduced fetal PO2 by 29%. Alpha 1 receptor blockade after phenoxybenzamine 5.0 mg/kg was confirmed by a lack of change in uterine blood flow to IV norepinephrine 30 micrograms before cocaine administration. After phenoxybenzamine, cocaine produced no increase in maternal or fetal MAP. However, total uterine blood flow decreased 44%, uterine vascular resistance increased 59%, FHR increased 36%, and fetal PO2 fell 18%. Because the fetal responses mimicked the maternal responses to cocaine both before and after phenoxybenzamine, phenoxybenzamine apparently crossed the placenta to block fetal alpha 1 receptors as well. Alpha 1-adrenergic receptor stimulation is the major mechanism for the maternal and fetal hypertensive responses to cocaine. Although cocaine produces uterine artery vasoconstriction primarily by alpha 1 adrenergic receptor stimulation, its vasoconstrictive effects may involve other vasoactive neurotransmitters, such as dopamine or serotonin.

Sonographically homogeneous echogenic amniotic fluid in detecting meconium-stained amniotic fluid.

A prospective study was performed to examine the hypothesis that sonographically homogeneous echogenic amniotic fluid (AF) may provide a marker for the presence of meconium-stained AF. Twenty term gestations in which homogeneous echogenic AF was demonstrated sonographically were compared with 40 cases with sonographically clear AF. Two cases in the study group had meconium-stained AF at delivery. All of the controls had clear fluid by amniocentesis (performed for lung maturation studies) immediately after the sonographic examination. Thus, homogeneous echogenic AF had a sensitivity of 100%, a specificity of 69%, a positive predictive value of 10%, and a negative predictive value of 100% in detecting meconium. We conclude that homogeneous echogenic AF does not necessarily detect meconium-stained AF.

Animal surgery: an adjunct to training in obstetrics and gynecology.

A resident in obstetrics and gynecology obtains adequate experience in basic gynecologic surgery during a 3-year training program, but the technical skill acquired in surgery of the bowel, bladder, ureters, and pelvic vessels is limited by the clinical material available. A program is described in which 3 animal models (dog, rabbit, cat) were used to expand the surgical skills of gynecology residents. The increased surgical competence and professional stimulation provided the residents by this program are shown to be both cost- and time-effective.

Calcium, magnesium, phosphorus, and parathyroid hormone interrelationships in pregnancy and newborn infants.

The ability to measure directly human parathyroid hormone (hPTH) and ionized calcium (Ca++) is of fundamental importance in understanding their interrelation in pregnancy and the newborn. hPTH and Ca++ progressively increase throughout pregnancy. Since Ca++ is the direct determinant of hPTH levels, a different "set point" appears to be operative throughout pregnancy. The newborn infant, on the other hand, has higher serum Ca++ levels than its mother, and the infant's plasma hPTH is suppressed to undetectable or low levels. Ca++, total serum Ca, magnesium, and phosphorus are all significantly elevated in the serum of the mother at delivery. An active transport mechanism of all these minerals appears to be operative and lowers the maternal serum levels at the termination of labor in relation to serum levels in the third trimester of pregnancy.

Prenatal sonographic diagnosis, Doppler velocimetric umbilical cord studies, and subsequent management of an acardiac twin pregnancy.

Sonographic prenatal diagnosis and management of a twin pregnancy complicated by acardius anceps of one twin and acute polyhydramnios is presented. To our knowledge, this is the first case of an acardiac twin gestation in which Doppler umbilical arterial velocimetric studies were obtained. These studies, performed at 29 weeks' gestation, demonstrated markedly different umbilical artery systolic to end-diastolic (S/D) ratios in the twins. This difference is explained by the vascular resistance reflected in the umbilical artery S/D ratios obtained on each twin. The healthy twin's S/D ratio represented the vascular resistance of the placenta and the perfused acardiac twin. Because of the reversed direction of blood flow in the acardiac twin's umbilical artery, this S/D ratio represented the vascular resistance of the acardiac twin. Planned preterm delivery resulted in survival of the healthy normal twin.

The occurrence of simultaneous fetal heart rate accelerations in twins during nonstress testing.

A prospective study was performed of 152 pairs of nonstress tests (NSTs) obtained simultaneously from both members of 52 twin gestations. Fifty-seven percent of the total fetal heart rate (FHR) accelerations occurred simultaneously in both twins. Between twins, the incidence of simultaneously occurring FHR accelerations was independent of gestational age, growth discordancy, or the type of placenta. For each twin, the number of FHR accelerations remained constant with increasing gestational age. These results may suggest that tactile communication exists in utero between twins.

Biparietal diameter/femur length ratio, cephalic index, and femur length measurements: not reliable screening techniques for Down syndrome.

Previous published reports have shown that fetuses affected with Down syndrome have normal biparietal diameter (BPD), high BPD-to-femur length ratio, and shorter femur length and occipitofrontal diameter. A retrospective comparison of the BPD, occipitofrontal diameter, cephalic index, femur length, and BPD/femur length ratio was made between 17 fetuses with Down syndrome diagnosed prenatally by second-trimester amniocentesis and 17 matched controls. The gestational age at sonographic evaluation in the two groups ranged from 15-23 weeks. The results of this study show no significant differences in the BPD, occipitofrontal diameter, cephalic index, femur length, and BPD/femur length ratio in the Down syndrome group when compared with controls. The sensitivity of BPD/femur length ratio as a screening technique for Down syndrome in this study was 18%, with a specificity of 94%. This sonographic method does not appear to be a useful screening parameter for Down syndrome.