R179H mutation in ACTA2 expanding the phenotype to include prune-belly sequence and skin manifestations.

Mutations in ACTA2 (smooth muscle cell-specific isoform of α-actin) lead to a predisposition to thoracic aortic aneurysms and other vascular diseases. More recently, the ACTA2 R179H mutation has been described in individuals with global smooth muscle dysfunction. We report a patient heterozygous for the mutation in ACTA2 R179H who presented with megacystis at 13 weeks gestational age and, at birth, with prune-belly sequence. He also had deep skin dimples and creases on his palms and soles, a finding not previously described but possibly related to ACTA2. To our knowledge, this is the first report of the R179H mutation in ACTA2 in a child with prune-belly sequence. We think the R179H mutation in ACTA2 should be included in the differential diagnosis of individuals presenting with the sequence without an identified mechanical obstruction. Furthermore, as ACTA2 R179H has been reported in patients with severe vasculomyopathy and premature death, we recommend that molecular testing for this mutation be considered in fetuses presenting with fetal megacystis with a normal karyotype, particularly if the bladder diameter is 15 mm or more, to allow expectant parents to make an informed decision.

Rivaroxaban versus placebo in patients with acute coronary syndromes (ATLAS ACS-TIMI 46): a randomised, double-blind, phase II trial.

BACKGROUND: Rivaroxaban is an oral direct factor Xa inhibitor that has been effective in prevention of venous thromboembolism in patients undergoing elective orthopaedic surgery. However, its use after acute coronary syndromes has not been investigated. In this setting, we assessed the safety and efficacy of rivaroxaban and aimed to select the most favourable dose and dosing regimen. METHODS: In this double-blind, dose-escalation, phase II study, undertaken at 297 sites in 27 countries, 3491 patients stabilised after an acute coronary syndrome were stratified on the basis of investigator decision to use aspirin only (stratum 1, n=761) or aspirin plus a thienopyridine (stratum 2, n=2730). Participants were randomised within each strata and dose tier with a block randomisation method at 1:1:1 to receive either placebo or rivaroxaban (at doses 5-20 mg) given once daily or the same total daily dose given twice daily. The primary safety endpoint was clinically significant bleeding (TIMI major, TIMI minor, or requiring medical attention); the primary efficacy endpoint was death, myocardial infarction, stroke, or severe recurrent ischaemia requiring revascularisation during 6 months. Safety analyses included all participants who received at least one dose of study drug; efficacy analyses were by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00402597. FINDINGS: Three patients in stratum 1 and 26 in stratum 2 never received the study drug. The risk of clinically significant bleeding with rivaroxaban versus placebo increased in a dose-dependent manner (hazard ratios [HRs] 2.21 [95% CI 1.25-3.91] for 5 mg, 3.35 [2.31-4.87] for 10 mg, 3.60 [2.32-5.58] for 15 mg, and 5.06 [3.45-7.42] for 20 mg doses; p<0.0001). Rates of the primary efficacy endpoint were 5.6% (126/2331) for rivaroxaban versus 7.0% (79/1160) for placebo (HR 0.79 [0.60-1.05], p=0.10). Rivaroxaban reduced the main secondary efficacy endpoint of death, myocardial infarction, or stroke compared with placebo (87/2331 [3.9%] vs 62/1160 [5.5%]; HR 0.69, [95% CI 0.50-0.96], p=0.0270). The most common adverse event in both groups was chest pain (248/2309 [10.7%] vs 118/1153 [10.2%]). INTERPRETATION: The use of an oral factor Xa inhibitor in patients stabilised after an acute coronary syndrome increases bleeding in a dose-dependent manner and might reduce major ischaemic outcomes. On the basis of these observations, a phase III study of low-dose rivaroxaban as adjunctive therapy in these patients is underway. FUNDING: Johnson & Johnson Pharmaceutical Research & Development and Bayer Healthcare AG.

Association of caesarean delivery for first birth with placenta praevia and placental abruption in second pregnancy.

OBJECTIVE: To quantify the risk of placenta praevia and placental abruption in singleton, second pregnancies after a caesarean delivery of the first pregnancy. DESIGN: Retrospective cohort study. SETTING: Linked birth and infant mortality database of the USA between 1995 and 2000. POPULATION: A total of 5,146,742 singleton second pregnancies were available for the final analysis after excluding missing information. METHODS: Multiple logistic regressions were used to describe the relationship between caesarean section at first birth and placenta praevia and placental abruption in second-birth singletons. MAIN OUTCOME MEASURES: Placenta praevia and placental abruption. RESULTS: Placenta praevia was recorded in 4.4 per 1000 second-birth singletons whose first births delivered by caesarean section and 2.7 per 1000 second-birth singletons whose first births delivered vaginally. About 6.8 per 1000 births were complicated with placental abruption in second-birth singletons whose first births delivered by caesarean section and 4.8 per 1000 birth in second-birth singletons whose first births delivered vaginally. The adjusted odds ratio (95% CIs) of previous caesarean section for placenta praevia in following second pregnancies was 1.47 (1.41, 1.52) after controlling for maternal age, race, education, marital status, maternal drinking and smoking during pregnancy, adequacy of prenatal care, and fetal gender. The corresponding figure for placental abruption was 1.40 (1.36, 1.45). CONCLUSION: Caesarean section for first live birth is associated with a 47% increased risk of placenta praevia and 40% increased risk of placental abruption in second pregnancy with a singleton.

Diagnosis of low-lying placenta: can migration in the third trimester predict outcome?

OBJECTIVES: To investigate the relationship between the rate of migration of a low-lying placenta during the third trimester and the eventual route of delivery. METHODS: All patients with a placenta lying within 3 cm of the internal cervical os or overlapping it on transvaginal ultrasound at > or = 26 weeks' gestation were included in the study. The exact distance between the center of the internal cervical os and the leading edge of the placenta was measured by transvaginal sonography, repeated at approximately 4-week intervals until delivery. RESULTS: The mean rates of migration in patients who had (n = 7) and who did not have (n = 29) Cesarean section for placenta previa were +0.3 mm/week and +5.4 mm/week, respectively (P < 0.0001). When the placental edge was initially > 20 mm from the internal os, migration occurred in all cases and no Cesarean section for placenta previa was performed. For those between -20 mm and +20 mm, sufficient migration to avoid Cesarean section occurred in 88.5% of cases. Beyond a 20 mm overlap, significant placental migration did not occur and all patients required Cesarean section. CONCLUSION: Placental migration may occur progressively throughout the third trimester. The initial position of the placental edge and the subsequent rate of migration can be used to predict the eventual route of delivery.

The effect of variable heart rate decelerations on intraventricular hemorrhage and other perinatal outcomes in preterm infants.

OBJECTIVE: We investigated the hypothesis that repetitive variable heart rate decelerations in labor are associated with an increased incidence of neonatal complications in premature infants. METHODS: This was a retrospective case-control study. Singleton fetuses weighing between 750 and 2500 g at 25-35 weeks' gestation were considered for the study. Fetuses delivered by Cesarean section prior to labor were excluded. Heart rate traces were retrieved from an electronic archive and were assessed for the presence of variable decelerations. Cases had at least three variable decelerations in the hour prior to delivery and were matched 1:1 with controls for gestation, sex and birth weight. RESULTS: A review of 6500 deliveries yielded 41 matched pairs. The groups were compared for the following outcomes. Measures of acute morbidity were cord pH at delivery, 5-min Apgar score and resuscitation; measures of chronic morbidity were intraventricular hemorrhage, periventricular leukomalacia, necrotizing enterocolitis and death. There was no difference in measures of acute morbidity between the groups. The incidence of chronic morbid outcome measures in the cases was six (15%) vs. one (2.5%) in controls (p = 0.01). CONCLUSIONS: This study suggests that variable decelerations in preterm infants are associated with chronic morbidity, particularly intraventricular hemorrhage through a mechanism independent of fetal acidemia. Further study is required to determine whether these infants would benefit from early Cesarean section.

Influence of an educational program on medical students' attitudes to substance use disorders in pregnancy.

Substance use disorders (SUDs) in pregnancy are becoming increasingly prevalent. Our study aimed to measure the effect of a teaching module on alcohol, tobacco, and drug use on the attitude of second year medical students toward pregnant women with SUDs. A questionnaire was administered to 84 medical students before a 5-week systems block on human reproduction, which included specific learning events related to SUDs. The questionnaire was readministered at the completion of the block. Pre- and postintervention scores were compared. Students showed significant improvement (p < .05, reliability coefficient 0.90) in their level of comfort in dealing with womenwith SUD in pregnancy. Other positive trends relating to attitudes toward drug- and alcohol-dependent women during pregnancy were also identified. SUD teaching interventions among medical students can improve their comfort level and attitude toward pregnant women with SUDs. This supports the current initiative of Project CREATE (Curriculum Renewal and Evaluation of Addiction Training and Education) to implement a comprehensive undergraduate SUD teaching program in Canadian medical schools.

Recent trends in fetal and infant outcomes following post-term pregnancies.

All births and infant deaths in 1985 87 and 1992 94 in Canada, except in Ontario and Newfoundland, were analyzed to assess the potential impact of the recent increased use of elective labour induction for post-term pregnancies. Probabilistic linkage was carried out of infant death records (Canadian Mortality Database) and respective birth registrations (Canadian Birth Database) for the periods 1985 87 and 1992 94. The combined fetal and infant mortality declined by 20 30% between 1985 87 and 1992 94 at each gestational week beginning at 37 weeks, with no increased reduction among post-term pregnancies. Asphyxia-related fetal and infant deaths, the most likely cause of death being preventable by labour induction for post-term pregnancies, did not decrease among post-term pregnancies. In contrary, a substantial decrease of asphyxia-related deaths was observed at 37 and 38 weeks over the same periods of time. Because fetal and infant deaths are rare events and because the number of pregnancies passing 42 weeks of gestation decreased dramatically during 1992 94, statistically unstable results may be inevitable in the comparison of mortality in this group of pregnancies.

The effect of income pooling within a call group on rates of obstetric intervention.

BACKGROUND: On July 1, 1997, the call group at a tertiary referral hospital in Ottawa changed its remuneration. The authors tested the hypothesis that change in an obstetric call group's remuneration from individual fee-for-service billing to equal sharing of the pooled group income would result in reduced rates of obstetric intervention. METHODS: Intervention rates were compared for the 12 months before (1678 births) and the 12 months after (1934 births) the change. Data were collected on onset of labour, indication for induction of labour, mode of delivery and neonatal outcome. Statistical analysis was performed with Wilcoxon's signed-rank test. RESULTS: The mean rate of elective induction of labour was 38.6% in the year before the change and 33.3% in the year after the change (p = 0.01). There were small but statistically significant increases in the mean duration of labour and mean length of the second stage (p = 0.03). INTERPRETATION: Billing policy may affect clinical decisions. Our findings add weight to the literature showing increased intervention rates with fee-for-service remuneration.

The relationship between cervical dilatation at initial presentation in labour and subsequent intervention.

OBJECTIVE: To examine the relationship between the cervical dilatation at which women present in labour and the subsequent likelihood of caesarean section. DESIGN: Retrospective cohort study. SETTING: University teaching hospital. POPULATION: 3,220 women met the entry criteria from 14,050 deliveries between January 1995 and December 1999. METHODS: Women meeting the following criteria were identified: those in spontaneous labour with a singleton pregnancy and a cephalic presentation at 37-42 weeks of gestation; all women delivering within 36 hours of first presentation were included. Women who had spontaneous rupture of the membranes before first attendance were excluded. MAIN OUTCOME MEASURES: The primary outcome was the rate of caesarean section. Secondary outcomes were operative vaginal delivery, fetal weight, cord pH, five minute Apgar score, length of labour, labour augmentation with oxytocin and epidural analgesia. RESULTS: The risk of caesarean section decreased with increasing cervical dilatation at presentation. This was true for nulliparous (n = 1,168) and parous women (n = 2,052). The caesarean section rate of nulliparous women presenting at 0-3cm (n = 812) was 10.3%, compared with 4.2% for those presenting at 4cm-10 cm (n = 356), and the mean duration of labour before presentation was 2.0 hours versus 4.5 hours, respectively (P = 0.0001). For parous women the caesarean section rates were 5.7% and 1.3%, respectively (P = 0.0001). There were significantly greater frequencies of use of oxytocin and epidural analgesia by women presenting earlier in labour. The caesarean section rate of 185 nulliparae (15.8%) who were initially allowed home was no different from those admitted immediately (9.2% vs 8.2%, P = 0.67). Similarly, 196 (9.5%) of multiparae went home and had a caesarean section rate of 3.6%, compared with 3.1% if admitted immediately (P = 0.76). CONCLUSIONS: Women who present to hospital at 0-3cm spend less time in labour before presentation and are more likely to have obstetric intervention than those presenting in more advanced labour. Outcomes were similar whether or not the woman was initially allowed home.

[Pulmonary vascular reactivity and the development of edema in the presence of prostaglandin inhibitors in the isolated canine lobe]. / Reactividad vascular pulmonar y formación de edema en presencia de inhibidores de prostaglandinas en el lóbulo canino aislado.

UNLABELLED: Alveolar hypoxia is the most powerful pulmonary vasoconstrictor. In a previous work, we did not demonstrate significant changes in vascular reactivity and edema formation in an isolated canine lobe model during alveolar hypoxia. The purpose of this study is to define vascular pulmonary reactivity and edema formation after induction of pulmonary vasoconstriction using a prostaglandin inhibitor like tiaprofenic acid and alveolar hypoxia. Six isolated canine pulmonary lobules were instrumented and studied, all of them under two conditions (normoxia FIO2 21% and hypoxia FIO2 5%) four starting in normoxia condition and 2 starting in hypoxia condition. RESULTS: No significant changes in filtration rate were found, normoxia 0.42 +/- 0.41, hypoxia 0.37 +/- 0.51 ml/min/100 g pulmonary tissue P = NS. The arterial pressure in basal conditions was 25.1 +/- 6.21, and during hypoxia increased to 37 +/- 7.19 cm H2O (Delta 12.0 +/- 1.2 cm H2O). P < 0.001. CONCLUSION: Hypoxia vascular reactivity was significantly increased in tiaprofenic acid pretreated isolated canine lobes, no changes in pulmonary permeability was found nor increased rate in edema formation.

Accuracy of strategies for monitoring fetal heart rate in labor.

We investigated whether the accuracy of auscultation could be improved with the use of a heart rate meter. Six fetal heart rate (FHR) traces were presented in a random sequence to 30 subjects using a customized computer program in each of three modalities: auscultation by counting alone, auscultation with the aid of an FHR meter, and visual assessment. The following characteristics were assessed: baseline rate, baseline variability, periodic change, and interpretation of the trace. For baseline rate, counting was associated with consistent underestimation of the FHR, which became more evident as the heart rate increased. The variation observed with each method was greatest with counting. For baseline variability, the proportion of correct responses using a meter was comparable to visual assessment, whereas counting was significantly less effective in 4 of 6 traces. For periodic change, the use of a meter was superior to counting in 4 of 6 traces, but both were inferior to visual assessment in 4 of 6 traces. In the interpretation of the trace, the use of a meter was again superior to counting, but both were inferior to visual assessment. Discrepancies were most marked in the least reassuring traces. Assessment of the FHR is significantly more accurate with the aid of a heart rate meter, and reduces interobserver variation.

The impact of measurement error on the comparison of two treatments using a responder analysis.

Investigators often report results of studies comparing the proportions of subjects who have clinically meaningful responses to various therapeutic regimens. When the outcome variable is a continuous measure this involves dichotomizing the observed response based on a predefined threshold value. The effect of this strategy is examined, paying particular attention to the impact of measurement error on the resulting estimates of treatment effect (difference in the proportion responding). Expressions are obtained for quantifying the magnitude and direction of the resulting bias, and these are illustrated in a study evaluating a pharmaceutical treatment for osteoporosis.

Spectroscopic approach to capillary-alveolar membrane damage induced acute lung injury.

BACKGROUND: Acute (or adult) respiratory distress syndrome (ARDS) is often associated with a high mortality rate in the critical care population. The term acute lung injury (ALI), a primitive phase of ARDS, was introduced by the European and American consensus groups to provide early diagnoses of ARDS. The pathophysiological characterization of ALI/ARDS - an increased pulmonary capillary-alveolar membrane barrier permeability - is generally not included in current intensive care unit diagnosis criteria. OBJECTIVES: To apply the infrared (IR) spectroscopic technique, in combination with the administration of hydroxyethyl starch (HES), to patients with ALI and ARDS. PATIENTS AND METHODS: This retrospective study involved 67 patients from the intensive care unit at the Health Sciences Centre, University of Manitoba, Winnipeg, Manitoba. The methodology was based on the IR spectroscopic determination of HES in patient's bronchial washing fluid. Exaggerated infiltration of HES into the alveolar space was taken as evidence of damage to the pulmonary capillary-alveolar membrane, which in turn provided a diagnosis of ALI/ARDS. RESULTS: The accuracy of determining pulmonary HES leakage in severe lung injury (Partial pressure of arterial oxygen/fraction of inspired oxygen [PaO2/FiO2] less than 100 mmHg [n=10]), was 100%. The subgroups with PaO2/FiO2 between 100 and 200 mmHg (n=23), and PaO2/FiO2 between 200 and 300 mmHg (n=22), 56.5% and 77.3%, respectively, showed IR positive for HES leakage. CONCLUSIONS: The proposed IR bronchial washing assay is very sensitive in determining the pulmonary HES leakage in severe lung injury. It is also suitable for evaluating pulmonary leakage at an early phase of the injury, a fact that is particularly important for supportive treatment. The method is advantageous because no radioactive tracers are employed, little sample preparation is required, and it is rapid and minimally invasive, making it convenient to use in the critical care environment.

Prevention of nonvertebral fractures by alendronate. A meta-analysis. Alendronate Osteoporosis Treatment Study Groups.

OBJECTIVE: To evaluate the effect of treatment with alendronate sodium, a potent aminobisphosphonate, on the incidence of nonvertebral fractures in postmenopausal women with osteoporosis. DATA SOURCES: Published data and data on file at Merck Research Laboratories. STUDY SELECTION: All completed prospective, randomized, placebo-controlled alendronate trials of at least 2 years' duration (5 studies). DATA EXTRACTION: All subjects were women with osteoporosis between the ages of 42 and 85 years, postmenopausal at least 4 years, with lumbar spine bone mineral density (measured using dual-energy x-ray absorptiometry) at least 2.0 SD below the mean for young adult women. All women randomized to treatment with placebo or alendronate at a dose higher than 1 mg per day for at least 2 years were included. DATA SYNTHESIS: In the placebo group (n=590), 60 women reported nonvertebral fractures during 1347 patient-years at risk (overall rate, 4.45 women with fractures per 100 patient-years at risk). In the alendronate group (n = 1012), 73 women reported nonvertebral fractures during 2240 patient-years-at risk (overall rate, 3.26 women with fractures per 100 patient-years at risk). The estimated cumulative incidence of nonvertebral fractures after 3 years was 12.6% in the placebo group and 9.0% in alendronate group. The relative risk for nonvertebral fracture estimated using the Cox proportional hazards model was 0.71 (95% confidence interval,0.502-0.997) (P=.048). A reduction in risk was consistent across each of the studies and at each major site of osteoporotic fracture, including the hip and wrist. CONCLUSION: In postmenopausal women with osteoporosis, treatment with alendronate reduces the risk of nonvertebral fractures over at least 3 years.

Response of ventilator-dependent patients to different levels of proportional assist.

Proportional-assist ventilation (PAV) is a form of ventilatory support in which airway pressure increases in proportion to patient effort. Because it effectively reduces the mechanical load to an adjustable extent, PAV permits the study of the pattern of breathing in patients with respiratory disease when unconstrained by abnormal respiratory mechanics. We studied 11 patients with assorted medical problems requiring ventilatory support. The patients were switched to PAV, and the level of support was varied from near-maximal levels to the lowest tolerable level. Each level was maintained for several minutes while ventilation (VE), tidal volume (VT), and respiratory rate (f) were monitored. The breathing pattern observed with the highest assist varied substantially among patients. The ranges (and means) of VE, VT, and f were 5.6-18.7 (12.8) l/min, 203-844 (517) ml, and 18-33 (25) breaths/min, respectively. The correlation between VT and VE at the highest assist was very high (r = 0.91), suggesting that ventilatory demand is the most important determinant of VT variability. There were no systematic changes in breathing pattern as the level of assist was altered; at the highest and lowest levels of support, VE, VT, and f were, respectively, 12.8 +/- 5.4 (SD) vs. 11.6 +/- 4.3 l/min, 517 +/- 217 vs. 459 +/- 175 ml, and 25.0 +/- 4.2 vs. 25.7 +/- 3.9 breaths/min. These results indicate that within each patient, in a given state, there exist unique values for a desired VE, VT, and f that are largely independent of the mechanical load; if assist is increased, patient effort is decreased to maintain the desired ventilatory targets.

[Continuous spectrophotometry as a method to study pulmonary edema in isolated canine pulmonary lobe]. / Espectrofotometría continua como método para el estudio del edema pulmonar en una preparación de lóbulo pulmonar canino aislado.

The aim of this paper is to introduce the spectrophotometric method to the study of pulmonary edema in isolated ex-vivo canine pulmonary lobe preparation. This spectrophotometric method is based on the on-line measure of light transmission in a column of blood, that is proportional to hematocrit. A second light is used to follow Evans blue dyed proteins. With this method we were able to measure the amount of edema in 10 isolated canine lobes. Both the filtration and reflection coefficient of the membrane as well as the characteristics of the filtrate could be calculated. The filtration coefficient was 0.6 +/- 0.4 ml/min (1.3 +/- 0.9 ml/min/100 g pulmonary, tissue) at maximum capillary pressure and the reflection coefficient was 0.53 +/- 0.07. With the spectrophotometric method we have the capability to study different aspects of lung edema formation. This method has the advantage of being exact and independent from pressure and volume induced vascular changes. It also allows the measurement of solute transport.

The excitation-adaptation model of pediatric chronic illness.

This article examines the value of the psychosomatic family model for the study of chronically ill children. Four conceptual problems arise in the discussion of this model: the unidirectional causality of the model; the function of the sick child for the family system; the pathology of the family characteristics; and the disease type. In the present study, we propose (a) that a distinction be made between uncontrolled and controlled forms of disease, and (b) that the family characteristics of "cohesion" and "adaptation" be examined in relation to the parental capacity for problem solving and the acceptance or rejection of the child by the parents. This is shown by means of empirical research. In this empirical study, 20 families with a child suffering from controlled asthma are compared with 20 families with a child suffering from uncontrolled asthma. Contrary to the assumptions derived from the psychosomatic family model, the results show significantly more cohesion and structure in the group with a child suffering from controlled asthma. The findings from this study are integrated in a new model for the study of chronic childhood illness--"the excitation-adaptation model." In this model, two circular processes are emphasized involving (a) the progress of the illness and the way in which parents and child deal with medication and medical advice (therapy compliance), and (b) the factors influencing the therapy compliance on the part of the parents, the family, and the child. By studying these factors in connection with the management of the illness, it should become clear whether family characteristics are adaptive or pathological.

Intractable or uncontrolled asthma: psychosocial factors.

The purpose of this study was to address the question of why, when there is a comparable severity of asthma, medical facilities, and treatments, some children develop controlled asthma whereas other children do not and are frequently ill. The major research questions pertained to whether families with a child with uncontrolled asthma differ from families with a child with controlled asthma as regards family characteristics and child-rearing attitudes, whether particular psychosocial variables relate to the severity of the asthma, and whether the interaction between the severity of the asthma and its controllability may clarify the role of psychosocial variables. Two studies were conducted, in which 70 asthmatic children (age range 9-15 years) and their families participated. The children and their caregivers were presented with measures assessing parental child-rearing attitudes, the problem-solving abilities of the caregivers, family functioning, and emotional disorders in the asthmatic children. Contrary to the assumptions derived from the psychosomatic family model, the findings of these studies suggest, among other things, that cohesion of family members and rigid manner of function of caregivers may have a positive rather than a negative influence on the welfare of the asthmatic child. In addition, controlled asthma was found to relate to the correct use of medication, which was predominantly evident in more structured and interdependent family environments. Of major importance is the conclusion that a distinction between controlled and uncontrolled asthma leads to a better insight into the role of psychosomatic variables than a distinction on the basis of the severity of the asthma.