Evaluation of the activated partial thromboplastin time assay for clinical monitoring of PEGylated recombinant factor VIII (BAY 94-9027) for haemophilia A.

Patients with haemophilia (PWH) are usually monitored by the one-stage activated partial thromboplastin time (aPTT) factor VIII (FVIII) assay. Different aPTT activators may affect clotting time (CT) and FVIII:C levels in patients treated with PEGylated FVIII. To evaluate the characteristics of PEGylated FVIII (BAY 94-9027) in various aPTT clotting assays, and to identify suitable aPTT reagents for monitoring BAY 94-9027 during the treatment of PWH, BAY 94-9027 and World Health Organization (WHO) 8th FVIII standards (WHO-8) were spiked into pooled and individual severe haemophilia A plasma at 1.0, 0.25 and 0.05 IU mL(-1) . Five commercial aPTT reagents widely used in clinical laboratories were compared and evaluated for BAY 94-9027 activity in plasma from PWH. BAY 94-9027 and WHO-8 bestowed similar CT and excellent precision when ellagic acid (SynthAFax, Dade Actin, and Cephascreen) aPTT reagents were used. In contrast, BAY 94-9027 showed significantly prolonged CT and poor precision compared with WHO-8 using silica aPTT reagents (APTT-SP and STA PTT 5). Furthermore, free 60-kDa polyethylene glycol (PEG), used for the conjugation of FVIII, showed a dose-dependent prolongation of CT in the APTT-SP assay. There was no effect on the SynthAFax-APTT, prothrombin time, or FXIa-initiated thrombin generation assay, demonstrating that the PEG moiety on FVIII has no general effect on the coagulation cascade. In summary, ellagic aPTT reagents (SynthAFax, Dade Actin, and Cephascreen) are most suitable for evaluating potency of BAY 94-9027 and should be the preferred aPTT reagents used in clinical laboratories for monitoring FVIII activity after infusion of BAY 94-9027 to PWH.

Pregnancy and active Huntington disease: a rare combination.

We describe the complicated course of a rare pregnant woman with symptomatic Huntington disease (HD) and discuss multidisciplinary care issues that may be encountered. A 31-year-old gravida 2, para 1 with advanced HD was admitted at 30 weeks gestation for preterm labor. Her course was complicated by progressive cognitive and physical impairment, dysphagia, malnutrition, diabetes insipidus, aspiration pneumonia, chorioamnionitis, preterm delivery and pyelonephritis. Pregnant women with symptomatic HD may present multiple challenges requiring extensive multidisciplinary input.

Effect of vaginal pH on efficacy of the controlled-release dinoprostone vaginal insert for cervical ripening/labor induction.

OBJECTIVE: To evaluate whether vaginal pH alters the efficacy of the controlled-release dinoprostone vaginal insert (Cervidil) for cervical ripening/labor induction. METHODS: Thirty-four women with an unfavorable cervix undergoing labor induction were enrolled in this prospective, double-blind investigation. Vaginal pH and Bishop score assessments were made by an independent examiner. All women received preinduction with the dinoprostone vaginal insert 10 mg intravaginally for 12 h. Twelve hours later, oxytocin induction initiated according to the standardized protocol and outcome data were collected. RESULTS: Mean (+/- SD) initial vaginal pH was 4.9 +/- 0.5 for the study cohort. No significant differences were noted between women with a high vaginal pH (> 4.5, n = 18) and those with a low vaginal pH (< or = 4.5, n = 16) with respect to maternal age, parity, gestational age, or initial Bishop score. Similarly, Bishop score change over the preinduction interval (3.2 vs. 3.3), time to active labor (28.6 vs. 24.6 h) and time to delivery (33.7 vs. 31.4 h) were not significantly different between the low and the high pH groups, respectively. Linear regression analysis revealed no significant association between vaginal pH and Bishop score change during the preinduction interval, time to active labor, time to complete dilatation, or time to delivery. CONCLUSION: Vaginal pH does not appear to influence the efficacy of the controlled-released dinoprostone vaginal insert for cervical ripening/labor induction.

Structure and seasonal dynamics of hyporheic zone microbial communities in free-stone rivers of the western United States.

The hyporheic zone of a river is characterized by being nonphotic, exhibiting chemical/redox gradients, and having a heterotrophic food web based on the consumption of organic carbon entrained from surface waters. Hyporheic microbial communities constitute the base of food webs in these environments and are important for maintaining a functioning lotic ecosystem. While microbial communities of rivers dominated by fine-grained sediments are relatively well studied, little is known about the structure and seasonal dynamics of microbial communities inhabiting the predominantly gravel and cobble hyporheic zones of rivers of the western United States. Here, we present the first molecular analysis of hyporheic microbial communities of three different stream types (based on mean base discharge, substratum type, and drainage area), in Montana. Utilizing 16S rDNA phylogeny, DGGE pattern analysis, and qPCR, we have analyzed the prokaryotic communities living on the 1.7 to 2.36 mm grain-size fraction of hyporheic sediments from three separate riffles in each stream. DGGE analysis showed clear seasonal community patterns, indicated similar community composition between different riffles within a stream (95.6-96.6% similarity), and allowed differentiation between communities in different streams. Each river supported a unique complement of species; however, several phylogenetic groups were conserved between all three streams including Pseudomonads and members of the genera Aquabacterium, Rhodoferax, Hyphomicrobium, and Pirellula. Each group showed pronounced seasonal trends in abundance, with peaks during the Fall. The Hyphomicrobium group was numerically dominant throughout the year in all three streams. This work provides a framework for investigating the effects of various environmental factors and anthropogenic effects on microbial communities inhabiting the hyporheic zone.

Chronology of neurological manifestations of prenatally diagnosed open neural tube defects.

OBJECTIVE: To evaluate the incidence and chronology of sonographic markers of neurological compromise in prenatally diagnosed neural tube defects. METHODS: We reviewed our ultrasound database from 1988 to 1999 to identify all cases of prenatally diagnosed neural tube defects. All patients received an initial detailed targeted ultrasound evaluation with subsequent evaluations every 4-6 weeks. Cases involving multiple congenital anomalies, aneuploidy, or inadequate follow-up were excluded. Specific ultrasound markers assessed included the presence of ventriculomegaly (> 10 mm) and clubfoot. RESULTS: Forty-seven cases of neural tube defects were identified over the study interval. After exclusions, 42 cases were available for evaluation. The overall incidence of ventriculomegaly and clubfoot in the study cohort was 86% and 38%, respectively. In the 33 patients with initial ultrasound examination performed at < 24 weeks' gestation, 76% (25/33) had evidence of ventriculomegaly and 30% (10/33) and clubfoot. Only 9% (1/11) of the patients managed expectantly developed evidence of ventriculomegaly and 3/11 (27%) developed clubfoot from the time of the initial ultrasound examination to delivery. CONCLUSIONS: Ultrasound markers of neurological compromise are early and frequent findings associated with fetal neural tube defects. Development of ventriculomegaly is an uncommon occurrence later in gestation, while the risk for developing clubfoot appears to increase as gestation progresses.

Elevated amniotic fluid ferritin levels are associated with inflammation-related pregnancy loss following mid-trimester amniocentesis.

OBJECTIVE: Occult infection accounts for up to 12% of pregnancy losses following genetic amniocentesis. Elevated serum and cervical fluid levels of ferritin, an acute-phase reactant, have been associated with spontaneous preterm delivery. We determined the association between amniotic fluid (AF) ferritin levels and post-amniocentesis pregnancy loss. METHODS: We performed a case-control study involving 66 women with a non-anomalous fetus who had a spontaneous pregnancy loss within 30 days following genetic amniocentesis and 66 term controls matched for maternal age, gestational age, time of test and indication for amniocentesis. Amniotic fluid ferritin and interleukin-6 (IL-6) levels were measured using commercially available kits. RESULTS: Mean (+/- SD) AF ferritin levels were similar between the cases (19.3 +/- 21.4 ng/ml) and the controls (19.8 +/- 22.7ng/ml) (p = 0.9). Mean (+/- SD) AF IL-6 levels were significantly higher in the women with post-amniocentesis pregnancy loss (4.0 +/- 13.1 ng/ml) than in controls (0.5 +/- 0.7 ng/ml) (p = 0.04). A significant proportion (12.1%, 8/66) of the women with post-amniocentesis pregnancy loss had elevated amniotic fluid IL-6 levels (> 3 SD, 2.5 ng/ml) indicating inflammation, as compared to none in the control group (p = 0.01). In this subgroup of women with pregnancy loss and elevated IL-6 levels, AF ferritin levels were significantly elevated (52.0 +/- 45.5 ng/ml) compared to the level in women who had a term delivery (19.8 +/- 22.7 ng/ml) (p = 0.002), and were strongly correlated with IL-6 levels among the cases (r = 0.67, p < 0.001). CONCLUSION: The strong correlation of AF ferritin with IL-6 levels, along with the high ferritin values in cases with high AF IL-6, indicates that ferritin is a marker of inflammation in asymptomatic women destined to have an early pregnancy loss.

The association of isolated mild fetal hydronephrosis with postnatal vesicoureteral reflux.

OBJECTIVE: We evaluated the incidence of vesicoureteral reflux in fetuses with prenatally detected isolated mild fetal hydronephrosis. METHODS: Fetuses with isolated mild fetal hydronephrosis (defined as a fetal renal pelvis anteroposterior diameter of > or = 4 and < 10 mm before 24 weeks' gestational age) were prospectively evaluated with postnatal renal ultrasound and voiding cystourethrography within the first few weeks after delivery. Infants were evaluated regardless of whether or not renal pelvic dilatation was seen on postnatal ultrasound examination. RESULTS: Forty cases of mild fetal hydronephrosis were identified from the 5,432 patients cared for at our institution from February 1996 to December 1998 (overall incidence: 1/136). Cases involving aneuploidy (n = 1) and inadequate follow-up (n = 5) were excluded from the investigation. One fetus with documented mild hydronephrosis early in gestation had spontaneous resolution and did not undergo postnatal evaluation. Of the remaining 33 infants, 32 underwent postnatal renal ultrasound examination and all had voiding cystourethrography. Vesicoureteral reflux was identified in five (15%) of the neonates. Eighty per cent (four out of five) of these infants were male. Resolution of vesicoureteral reflux occurred in 75% (three out of four) of the infants available for follow-up within 2 years of birth. CONCLUSIONS: Isolated mild fetal hydronephrosis is associated with vesicoureteral reflux on postnatal voiding cystourethrography.

Lethal pulmonary hypoplasia after in-utero myelomeningocele repair.

BACKGROUND: In-utero surgical repair of fetal myelomeningocele has been performed as a means to improve the postnatal condition of affected infants. CASE: A nulliparous woman underwent in-utero surgical repair of a fetal lumbosacral myelomeningocele at 24 weeks' gestation. Her postoperative convalescence was complicated by pulmonary edema, abdominal pain, chronic oligohydramnios, and preterm labor. The infant was delivered by cesarean at 33 weeks' gestation, but expired from respiratory distress caused by pulmonary hypoplasia at 9 hours of age. CONCLUSION: Until the benefits of in-utero repair of fetal myelomeningoceles are determined by well-controlled clinical trials, this technique remains investigational. Physicians and their patients who are considering this procedure must be fully aware of the potential risks that can occur.

Cardiac disease in pregnancy.

Cardiovascular adaptations of pregnancy are generally well tolerated in the healthy gravida; however, these changes can place undue stress on women with underlying cardiovascular disease and can result in increased risk for morbidity and mortality. In this article, we will review issues related to preconceptional counseling, cardiovascular adaptations of pregnancy, and the prognosis and management of the gravida with cardiac disease in pregnancy.

Magnesium sulfate as a tocolytic agent.

Although magnesium sulfate is widely used as a tocolytic agent in the hope of preventing spontaneous preterm birth, there is a paucity of data from large well-designed randomized clinical studies demonstrating the efficacy of magnesium sulfate therapy. Given the potential for untoward side effects and the inherent risks of magnesium sulfate therapy, a thorough understanding of the potential risks and benefits of this agent is needed. To accomplish this understanding we have provided a detailed review the history, pharmacology, physiology, maternal/fetal side effects, and tocolytic efficacy of magnesium sulfate.

Combined upper and lower extremity deep venous thrombosis.

In order to elucidate the natural history of upper extremity deep venous thrombosis (UEDVT), we compared the morbidity and mortality of patients with UEDVT and that of patients with both UEDVT and lower extremity deep venous thrombosis (LEDVT). Between 1993 and 1996, 21 patients presented to our institution with both LEDVT and UEDVT (Group 1). During the same time period, 144 patients were diagnosed with UEDVT alone (Group 2). The diagnosis was confirmed by duplex scanning in all patients. In Group 1, there were 14 females (67%) and 7 males (23%) with ages ranging from 25 to 97 yr old [mean 73 yr old +/-17 yr (SD)]. In Group 2, there were 84 females (58%) and 60 males (42%) with ages ranging from 9 to 101 yr old [mean 67 yr old +/-17 yr (SD)]. Differences in age and sex between the two groups were not statistically significant. In Group 1, systemic anticoagulation was implemented in 17 patients (81%). Two patients (9.5%) required placement of a SVC and IVC filters due to contraindication to anticoagulation. One patient did not receive anticoagulation, and one patient was only started on aspirin. In Group 2, treatment consisted of systemic anticoagulation in 94 patients (65%). The remainder of the patients were treated with aspirin in three patients (2%) or no anticoagulation in 31 patients (19%). Sixteen patients (11%) underwent placement of a SVC filter either due to failure of anticoagulation to prevent pulmonary embolism (two patients) or contraindication to anticoagulation (14 patients). Pulmonary emboli were documented by ventilation/perfusion lung scan in two patients (9.5%) in Group 1 and in 16 patients (11%) in Group 2. In the first group, 8 of the 21 patients (38%) were dead within 1 month of the diagnosis of UEDVT, and 11 of 21 patients (52%) were dead within 2 months of the diagnosis of UEDVT. In the second group, 20 of 144 patients (14%) were dead within 1 month of the diagnosis of UEDVT and 38 of 144 patients (26%) were dead within 2 months of diagnosis (P<0.02). Our data suggest that patients with both UEDVT and LEDVT have a higher mortality than patients with UEDVT alone. As the risk for pulmonary embolism is similar in both groups, we speculate that the severity of medical illness in patients with both UEDVT and LEDVT may contribute to the higher mortality. This is the first study to examine the mortality of this group of patients.

From concept to culture: the WWAMI program at the University of Washington School of Medicine.

Shortages of primary care physicians have historically affected rural areas more severely than urban and suburban areas. In 1970, the University of Washington School of Medicine (UWSOM) administrators and faculty initiated a four-state, community-based program to increase the number of generalist physicians throughout a predominantly rural and underserved region in the U.S. Northwest. The program developed regional medical education for three neighboring states that lacked their own medical schools, and encouraged physicians in training to practice in the region. Now serving five Northwest states (Washington, Wyoming, Alaska, Montana, and Idaho), the WWAMI program has solidified and expanded throughout its 30-year history. Factors important to success include widespread participation in and ownership of the program by the participating physicians, faculty, institutions, legislatures, and associations; partnership among constituents; educational equivalency among training sites; and development of an educational continuum with recruitment and/or training at multiple levels, including K--12, undergraduate, graduate training, residency, and practice. The program's positive influences on the UWSOM have included historically early attention to primary care and community-based clinical training and development of an ethic of closely monitored innovation. The use of new information technologies promises to further expand the ability to organize and offer medical education in the WWAMI region.

In utero erythrocyte transfusion for fetal xerocytosis associated with severe anemia and non-immune hydrops fetalis.

Hereditary xerocytosis is a rare hemolytic anemia occurring secondary to a defect in cell membrane potassium flux. We report a case of severe fetal anemia and non-immune hydrops secondary to hereditary xerocytosis that was managed successfully with in utero erythrocyte and albumin transfusion.

Pneumonia in pregnancy.

Although the advent of broad-spectrum antibiotics has markedly improved the maternal outcomes of pneumonia complicating pregnancy, pneumonia remains a significant condition that may complicate pregnancy. This article has reviewed the inherent physiologic respiratory changes that accompany pregnancy and the common causes of pneumonia in the pregnant woman. The clinical course of bacterial pneumonia seems to be minimally altered by pregnancy, whereas viral pneumonia carries a significantly worse prognosis when encountered during gestation. Prompt diagnosis, the initiation of respiratory support, and appropriate antimicrobial/antiviral therapy are key components of therapy for women in whom pregnancy is complicated by pneumonia. Because preterm labor frequently accompanies pneumonia, women should be monitored closely for the occult onset of preterm labor and appropriate interventions initiated if indicated. Perhaps even more important than interventions to treat acute pneumonia are efforts directed at active immunization or prophylactic therapy to prevent the development of pneumonia in select patient populations. The combination of these efforts is essential to optimize medical care for pregnant women.

Disease of the gallbladder and pancreas in pregnancy.

Although maternal mortality and morbidity are substantially lower today than decades ago, perinatal mortality and morbidity secondary to gallbladder and pancreatic disease remain excessive. Improvements in perinatal mortality reflect improvements in neonatal intensive care because most of the morbidity stems from prematurity. Prompt recognition of cholelithiasis and pancreatitis and liberal hospitalization have been associated with a decline in poor outcomes. The decision to switch from medical to surgical management must be made individually, taking into account past history, gestational age, and the response of current disease to conservative therapy.

Communicating with dying patients within the spectrum of medical care from terminal diagnosis to death.

BACKGROUND: Efforts to improve communication between physicians and dying patients have been unsuccessful, and guidelines for improving patient-physician communication about end-of-life care are based primarily on expert opinion. This study assessed which aspects of communication between patients and physicians are important in end-of-life care. METHODS: Twenty focus groups were held with 137 individuals, including patients with chronic and terminal illnesses, family members, health care professionals from hospice or acute care settings, and physicians with expertise in end-of-life care. Focus group analyses determined domains of physician skill at end-of-life care. Communication with patients was identified as one of the most important domains. Analyses of components important in communicating with dying patients and their families were performed. RESULTS: The following 6 areas were of central importance in communicating with dying patients: talking with patients in an honest and straightforward way, being willing to talk about dying, giving bad news in a sensitive way, listening to patients, encouraging questions from patients, and being sensitive to when patients are ready to talk about death. Within these components, subthemes emerged that provide guidelines for physicians and educators. Dying patients also identified the need to achieve a balance between being honest and straightforward and not discouraging hope. CONCLUSIONS: Several areas emerged for physicians to focus their attention on when communicating with dying patients. These findings provide guidance in how to improve this communication. They also highlight the need to approach communication about end-of-life care as a spectrum that requires attention from the time of a terminal diagnosis through death.

Understanding physicians' skills at providing end-of-life care perspectives of patients, families, and health care workers.

BACKGROUND: A framework for understanding and evaluating physicians' skills at providing end of life care from the perspectives of patients, families, and health care workers will promote better quality of care at the end of life. OBJECTIVE: To develop a comprehensive understanding of the factors contributing to the quality of physicians' care for dying patients. DESIGN: Qualitative study using focus groups and content analysis based on grounded theory. SETTING: Seattle, Washington. PARTICIPANTS: Eleven focus groups of patients with chronic obstructive pulmonary disease, AIDS, or cancer (79 patients); 3 groups of family members who had a loved one die of chronic disease (20 family members); 4 groups of nurses and social workers from hospice or acute care settings (27 health care workers); and 2 groups of physicians with expertise in end-of-life care (11 physicians). RESULTS: We identified 12 domains of physicians' skills at providing end-of-life care: accessibility and continuity; team coordination and communication; communication with patients; patient education; inclusion and recognition of the family; competence; pain and symptom management; emotional support, personalization; attention to patient values; respect and humility; and support of patient decision making. within these domains, we identified 55 specific components of physicians' skills. Domains identified most frequently by patients and families were emotional support and communication with patients. Patients with the 3 disease groups, families, and health care workers identified all 12 domains. Investigators used transcript analyses to construct a conceptual model of physicians' skills at providing end-of-life care that grouped domains into 5 categories. CONCLUSIONS: The 12 domains encompass the major aspects of physicians' skills at providing high-quality end-of-life care from the perspectives of patients, their families, and health care workers, and provide a new framework for understanding, evaluating, and teaching these skills. Our findings should focus physicians, physician-educators, and researchers on communication, emotional support, and accessibility to improve the quality of end-of-life care.

Delayed postpartum hemorrhage: a rare presentation of carbon monoxide poisoning.

A 41-year-old woman presented with postpartum hemorrhage and altered mentation. A markedly elevated serum carboxyhemoglobin level was noted. Oxygen therapy was initiated with resolution of the patient's bleeding and improved mental status. Carbon monoxide poisoning is a rare and previously unreported cause of postpartum hemorrhage resulting from a unique pathophysiologic mechanism.

Routine preoperative carotid duplex scanning in patients undergoing open heart surgery: is it worthwhile?

It has been reported that carotid screening may be cost-effective in patient populations in which the prevalence of severe carotid stenosis exceeds 4.5%. In order to identify potential patient populations who might benefit from carotid screening, we examined the results of preoperative duplex scanning in patients undergoing open heart surgery. Between January 1995 and July 1998, 3708 patients (59% male, 41% female) underwent open heart surgery at our institution. Of these, 3081 underwent coronary artery bypass grafting (CABG), 364 underwent valve replacement (VR), and 263 underwent CABG and VR. The ages of these patients ranged from 40 years to 98 years (mean 68 +/- 11 years). The risk factors analyzed included hypertension (HTN), 59%; smoking (Smk), 53%; and diabetes (DM), 33%. Patients were divided into three groups according to their age. Group A consisted of the 835 patients who were < or = 60 years old, group B consisted of 2474 patients ranging from 61 years to 80 years old, and group C consisted of 399 patients who were > or = 81 years old. All patients underwent bilateral preoperative carotid duplex scans at an Intersocietal Commission for the Accreditation of Vascular Laboratories (ICAVL)-accredited vascular laboratory. Statistical analyses were performed using chi-squared, Fisher's exact test, linear regression, and multivariate analysis. From our results we concluded that carotid screening is not recommended for patients under 60 years of age who are undergoing CABG unless they present with a minimum of two of the following major risk factors: hypertension, diabetes, or smoking. However, carotid screening is recommended for all patients undergoing open heart operations who are over the age of 60 years old, regardless of the absence of associated risk factors.