Near miss maternal morbidity.

Audit of severe maternal morbidity is a potent tool in determining standards of maternity care. This study determines the incidence of severe acute maternal morbidity in our population, identifies the underlying organ dysfunction and associated obstetric risk factors, and compares them to published international reports. Over a 5 year period, 1999-2003, data were collected prospectively from patients with severe acute maternal morbidity. There were 36,802 women who delivered infants weighing more than 500 g over the 5 years with 53 cases of severe maternal morbidity. There were two indirect maternal deaths yielding an incidence of 1.4/1000 for severe maternal morbidity and 5.4/100,000 for maternal mortality. The severe maternal morbidity to mortality ratio was 26.5:1. Massive obstetric haemorrhage requiring acute blood transfusion of > or = 5 units of packed red cells occurred in 77% of cases. This study identifies the feasibility of audit of severe maternal morbidity using simple defined clinical criteria. The incidence and underlying aetiology of severe maternal morbidity in our unit is comparable to other developed countries. It is essential that data on severe maternal morbidity are reviewed and analysed continuously at local hospital and national level to assess, maintain and improve clinical standards.

Obesity and mode of delivery in primigravid and multigravid women.

Our objective was to study the effects of maternal body mass index (BMI) on the mode of delivery for primigravid and multigravid women. A retrospective cohort study was conducted at the University College Hospital Galway, Ireland, of 5162 women delivered from 2001 to 2003. BMI at the first antenatal appointment was calculated. Comparisons were made between each of the five BMI categories separately for primigravid and multigravid women in relation to gestation at delivery, age, mode of delivery, and birthweight. There were 5162 deliveries during the time period of the study; 2006 were primigravid and 3156 were multigravid women. Overall, 2.6% of women were underweight, 49.2% were normal weight, 22.8% were overweight, 19.8% were obese, and 5.6% were morbidly obese. In comparison with women of normal weight, for overweight and obese women, there was a progressive reduction in vaginal delivery rate with increasing BMI. For morbidly obese primigravida, this reduction was by 33.5% (from 83.1% to 55.3%, chi2 = 39.84, P < 0.001), and for multigravida was by 23.6% (from 86% to 65.7%, chi2 = 53.05, P < 0.001). Obesity conferred a two- to threefold increased risk of delivery by emergency caesarean section for both primigravid (obese, relative risk [RR] 2.16, 95% confidence interval [CI] 1.72 to 2.73; morbidly obese, RR 2.30, CI 1.61 to 3.37) and multigravid women (obese, RR 1.97, CI 1.45 to 2.67; morbidly obese, RR 2.44, CI 1.61 to 3.69). We concluded that increasing maternal BMI exerts a progressive adverse effect on vaginal delivery rates for both primigravid and multigravid women. Obese primigravida should be counseled antenatally about the 30% risk of emergency caesarean section.

Preclinical safety evaluation of monoclonal antibodies.

Monoclonal antibodies (mAbs) are a well-established product class of biotechnology-derived pharmaceuticals for treating multiple diseases. A growing number of mAbs are being tested in clinical trials worldwide. Many of the second generation mAbs entering the clinic today are highly engineered, produced from recombinant cell lines, and present new safety challenges for regulators and industry scientists responsible for their safety evaluation. The increasing complexity of antibodies and the variety of recombinant production cell systems used for antibody manufacturing require a well thought-out approach for preclinical safety evaluation of mAbs. The focus of this chapter is to provide the reader with a basic framework for preparing a scientifically sound preclinical package for safety evaluation of therapeutic mAbs. We outline the general considerations for planning a preclinical program and the issues critical for success. We describe the types of preclinical safety studies and the timing for their conduct in relation to clinical trials. We also share some of the lessons learned about toxicity of mAbs from previous antibody development programs. A list of relevant regulatory documents issued by various government agencies and selected references to other useful texts and publications are also provided in the chapter. We believe that applying the principles described in this chapter will improve the quality and relevance of the preclinical safety data generated to support the future development of mAbs therapeutics.

Prenatal screening and diagnosis.

In Ireland there is no accepted national policy on the provision of prenatal screening and diagnosis and the availability of such tests is inconsistent. The aim of this study was to assess contemporary practice patterns of consultant obstetricians, specialist registrars in obstetrics and gynaecology and general practitioners regarding prenatal screening and diagnosis. A questionnaire was mailed to all 130 consultant obstetricians and gynaecologists, all 38 specialist registrars and to a random sample of 600 general practitioners, extracted from their database by the Irish College of General Practitioners. Data from the returned questionnaires was analysed using SPSS V.12.10. (SPSS inc., Chicago, IL). Overall 768 questionnaires were distributed with a response rate of 48% (371). Seventy five percent of respondants felt that patient demand for screening and diagnosis of fetal abnormalities has significantly increased compared with 5 years ago. Seventy two percent of respondants felt that detailed ultrasound examination of the fetus should be provided to all obstetric patients, irrespective of risk factors. However only 10% of respondants routinely discuss screening for fetal aneuploidy with antenatal patients. All agreed that depending on the particular patient, both invasive diagnostic and non-invasive screening tests should be available to patients. While it is reassuring that the majority of obstetricians support routine sonographic screening for fetal anatomy, there is a lack of consensus and knowledge regarding contemporary approaches to screening for fetal aneuploidy.

Selective cerebral vascular dysfunction in Mn-SOD-deficient mice.

We tested the hypothesis that the mitochondrial form of superoxide dismutase [manganese superoxide dismutase (Mn-SOD)] protects the cerebral vasculature. Basilar arteries (baseline diameter approximately 140 microm) from mice were isolated, cannulated, and pressurized to measure vessel diameter. In arteries from C57BL/6 mice preconstricted with U-46619, acetylcholine (ACh; an endothelium-dependent vasodilator) produced dilation that was similar in male and female mice and abolished by an inhibitor of nitric oxide synthase. Vasodilation to ACh was not altered in heterozygous male or female Mn-SOD-deficient (Mn-SOD+/-) mice compared with wild-type littermate controls (Mn-SOD+/+). Constriction of the basilar artery to arginine vasopressin, but not KCl or U-46619, was increased in Mn-SOD+/- mice (P<0.05), and this effect was prevented by tempol, a scavenger of superoxide. We also examined responses of cerebral (pial) arterioles (branches of the middle cerebral artery, control diameter approximately 30 microm) to ACh in anesthetized mice using a cranial window. Responses to ACh, but not nitroprusside (an endothelium-independent agonist), were reduced (P<0.05) in cerebral arterioles in Mn-SOD+/- mice, and this effect was prevented by tempol. Thus these are the first data on the role of Mn-SOD in cerebral circulation. In the basilar artery, ACh produced nitric oxide-mediated dilation that was similar in male and female mice. Under normal conditions in cerebral arteries, responses to ACh were not altered but constrictor responses were selectively enhanced in Mn-SOD+/- mice. In the cerebral microcirculation, there was superoxide-mediated impairment of responses to ACh.

Effect of mechanical ventilation on carotid artery thrombosis induced by photochemical injury in mice.

BACKGROUND: Increasing use of transgenic and gene targeting techniques for the investigation of hemostasis and vascular biology has generated interest in experimental models of carotid artery thrombosis in mice. OBJECTIVES: We tested the hypothesis that hypoventilation in anesthetized mice may cause hypercapnia, increased carotid artery blood flow, and altered thrombotic responses to photochemical injury of the carotid artery. METHODS: Arterial blood gases and carotid artery blood flow were measured in pentobarbital-anesthetized BALB/c or C57BL/6 J mice with and without mechanical ventilation. Photochemical injury of the carotid artery was induced using the rose bengal method. RESULTS: Compared with ventilated mice, unventilated mice had a 45% increase in carotid artery blood flow (0.74 +/- 0.04 vs. 0.41 +/- 0.03 mL min-1; P < 0.001) that was associated with an elevation of arterial PCO2 (58 +/- 4 vs. 33 +/- 4 mmHg; P < 0.05) and a decrease in arterial pH (7.18 +/- 0.05 vs. 7.32 +/- 0.03; P < 0.05). Time to first occlusion of the carotid artery after photochemical injury was shorter in ventilated than in unventilated mice (29 +/- 6 vs. 73 +/- 9 min; P < 0.001). Time to stable occlusion was also shorter in ventilated mice (49 +/- 8 vs. 81 +/- 6 min; P < 0.05). Elevated carotid artery blood flow, hypercarbic acidosis, and prolonged occlusion times also were observed in mice ventilated with supplemental carbon dioxide. CONCLUSIONS: General anesthesia without mechanical ventilation has the potential to confound studies of experimental thrombosis in vivo by producing hypoventilation, hypercapnia, acidosis, and altered carotid artery blood flow. Mechanical ventilation with maintenance of normal blood gases may enhance the physiological insight gained from experimental models of carotid artery thrombosis in mice.

Pregnancy complicated by a suburethral sling: a case report.

Incontinence surgery is rarely performed prior to the completion of a woman's childbearing. The literature is sparse in regard to women with prior incontinence surgery. There are no reports of pregnancy complicated by a sling procedure. A 26-year-old gravida 3, para 2-0-0-2 with prior surgical history of a Pereyra urethropexy followed by a Vesica suburethral sling, was referred at 18 weeks' gestation for assessment of the sling. Her antenatal course was complicated by pyelonephritis and intermittent urethral obstruction requiring Foley catheter placement. She delivered by scheduled cesarean section at 37 weeks' gestation. Three months following delivery she presented with pyelonephritis and recurrence of her incontinence. Pregnancy complicated by prior suburethral sling procedure may result in urinary outlet obstruction, pyelonephritis and disruption of the surgical repair.

Use of methergine for the prevention of postoperative endometritis in non-elective cesarean section patients.

OBJECTIVE: Methergine increases constriction of uterine musculature which may facilitate sloughing of endometrial debris, close uterine vessels, and prevent post-cesarean endometritis. The objective of this study was to evaluate the efficacy of methergine in preventing endometritis in patients undergoing non-elective cesarean section delivery. METHODS: Eighty patients undergoing non-elective cesarean section were enrolled in a prospective randomized clinical trial of methergine (41) versus no methergine (39) administration during the postpartum period. The hospital records were abstracted after discharge to compare the postpartum course. RESULTS: There were no significant demographic differences between the two groups. The women receiving methergine had a significant reduction in the rate of postoperative endometritis (10% vs. 36%, P < 0.005). In addition, the mean postoperative hemoglobin was significantly higher in the methergine treated group (P < 0.001). CONCLUSIONS: The use of methergine postpartum in women undergoing non-elective cesarean sections significantly reduces the incidence of postoperative endometritis and blood loss.

Management of a broken needle at the time of laparoscopic burch.

Loss of surgical instrumentation in endoscopic procedures poses problems not faced in traditional surgery. We describe the breakage and subsequent recovery of a 2-mm segment of needle from an Autosuture Endostitch device (U.S. Surgical) during a laparoscopic Burch urethropexy.

Lymphogranuloma venereum presenting as a rectovaginal fistula.

Lymphogranuloma venereum (LGV) is a rare form of the sexually transmitted disease caused by Chlamydia trachomatis. In the United States, there are fewer than 350 cases per year. In a review of the world's literature, there has not been a case reported in the last thirty years of a case of LGV presenting as a rectovaginal fistula. We present a case of an otherwise healthy American woman who presented with a rectovaginal fistula. Although uncommon, LGV does occur in developed countries and may have devastating tissue destruction if not recognized and treated before the tertiary stage.

Gene therapy for hemophilia.

Hemophilia is a genetically inherited bleeding disorder caused by a deficiency of the blood clotting factors VIII (hemophilia A) or IX (hemophilia B). Hemophiliacs suffer prolonged bleeding which can be life threatening and often leads to chronic disabilities. Current hemophilia treatment involves infusions of plasma-derived or recombinant clotting factor in response to bleeding crises. Prophylactic treatment is not available and current treatments remain problematic. The development of a gene therapy for hemophilia has been under investigation for the past decade. An overview is presented of the initial efforts using retroviral and adenoviral vectors for ex vivo and in vivo gene delivery strategies, respectively. Recent progress in developing FIX and FVIII adeno-associated virus vectors is reviewed. Sustained expression of therapeutic levels of FIX and FVIII have been demonstrated in mice. Phenotypic correction of hemophilia B has been shown in the murine and dog models of disease. A phase I human clinical trial has been initiated involving intramuscular injection of FIX. Prospectsfor hemophilia gene therapy look bright and the hopefor a cure has now moved from the realm of the possible to the probable.

Generation of recombinant adeno-associated viruses for delivery of genes into vascular cells.

A variety of delivery systems, both viral and nonviral, have been employed to genetically modify vascular endothelial cells and smooth muscle cells (SMC) in vitro and by direct in vivo gene transfer into the vessel wall. The most recent addition to gene delivery technology for the vasculature has been the use of adeno-associated virus (AAV) vectors (1-5).

Minilaparotomy hysterectomy.

OBJECTIVE: This article reports our experience with minilaparotomy hysterectomy. STUDY DESIGN: Minilaparotomy was defined as a skin incision < or = 6 cm in length. From January 1, 1996, to June 30, 1997, data were collected on all patients who underwent hysterectomy by means of a minilaparotomy. RESULTS: During the study a total of 250 hysterectomies were performed. Twenty-six of those were performed by means of a minilaparotomy. The mean age of the patients was 54 years. Seven had endometrial cancer and 8 had an adnexal mass. In 1 patient the incision was extended for staging of an ovarian cancer. The only intraoperative complication was rupture of a 6-cm ovarian tumor. After operation, 2 patients had febrile morbidity, 1 had a prolonged ileus, and in 1 atrial fibrillation developed. The mean uterine weight was 123 g. Median day of Foley catheter removal and mean day of ambulation, regular diet, and discharge were 1 day, 1.2 days, 2.4 days, and 3.4 days, respectively. CONCLUSION: Minilaparotomy is a safe and feasible route of hysterectomy for a selected group of patients.

GaLV pseudotyped vectors and cationic lipids transduce human CD34+ cells.

High transduction frequency of hematopoietic stem/progenitor cells is essential to derive clinical benefits for treating certain inherited and acquired diseases. We demonstrate here stable gene transfer into human bone marrow-derived CD34+ progenitors using cationic lipids to facilitate GaLV and amphotroic pseudotyped retroviral-mediated transductions. Furthermore, the transgene was detected only in the progeny of flow cytometer sorted CD34+ population transduced by the LAPSN (PG13) viral vector in the presence of cationic lipids but not when transduction was facilitated with conventional polycations Polybrene or protamine sulfate. Thus, a combination of GaLV pseudotyped vectors and cationic lipids results in increased transduction frequencies of the CD34+ cells without a requirement of extended in vitro culture, or co-cultivation with producer cell lines. These improvements may result in the production of therapeutically significant quantities of genetically modified hematopoietic cells.

Adeno-associated virus vectors for vascular gene delivery.

A variety of delivery systems have been used to genetically modify vascular endothelial cells and smooth muscle cells (SMCs), but currently available systems suffer from either inefficient in vivo gene transfer, transient episomal vector expression, or significant immune responses and inflammation. In the present study, we evaluated an alternate vector system, recombinant adeno-associated virus (rAAV) for transduction of vascular cells in culture and in vivo. Primary cultures of rabbit, monkey, and human SMCs; macaque and human microvascular endothelial cells; and human umbilical vein endothelial cells were efficiently transduced at a dose of 100 to 1000 DNase-resistant particles per cell. rAAV-mediated transduction of the vasculature in vivo was observed after intraluminal gene delivery or after intra-adventitial injection in carotid arteries of atherosclerotic cynomolgus monkeys. Whether vector delivery was intraluminal or adventitial, transduction was observed in the adventitia, particularly within microvessels (vasa vasorum) but not in cells of the intima or media. Transduction of adventitial microvessels was enhanced by balloon injury 4 days before gene transfer. This was particularly true for adventitial delivery. We have previously shown that adventitial cell proliferation increases significantly 4 days after balloon injury (45%) in this animal model. Together, these data suggest that cell proliferation may enhance AAV transduction in vivo in the vasculature. AAV vectors exhibited a tropism in vivo for the microvascular endothelium at the doses used in the present study, which may provide the opportunity for targeting gene delivery. In summary, we have demonstrated the utility of rAAV vectors for ex vivo vascular cell gene delivery and present an initial experience with rAAV for in vivo vascular gene delivery. This alternate vector system may overcome some of the limitations hampering the development of gene therapy for vascular disorders.

Maternal death from postpartum necrotizing fasciitis arising in an episiotomy: a case report.

BACKGROUND: Necrotizing fasciitis is a rare condition. We report a fatal case arising from an episiotomy in a previously healthy woman. CASE: A healthy 23-year-old prima gravida white female underwent vaginal delivery with repair of a proctoepisiotomy. Eighty-four hours postpartum, she developed increasing perineal swelling with severe pain. She presented on the 4th postpartum day with edema, erythema localized to the perineum, and vital signs significant only for tachycardia of 120/min. With a leukocytosis of 45,000/mul (87%) neutrophils, she was admitted to the hospital with an initial diagnosis of perineal cellulitis and empirically started on broad-spectrum intravenous antibiotic therapy. The patient's condition continued to deteriorate and she was then transferred to our facility on postpartum day 9 where a team performed two radical debridements of all necrotic tissue. Despite this and a broadened antibiotic coverage, the patient eventually experienced cardiopulmonary arrest and died on postpartum day 12. CONCLUSION: Necrotizing fasciitis must be considered in the differential diagnosis of the postpartum patient presenting with severe vulvar pain and erythema. Our patient exemplifies the obscure presentation with seemingly minimal skin changes. Any delay in diagnosis and treatment, which must include expeditious aggressive surgical debridement, will likely result in severe morbidity or mortality.

New prospects for cardiovascular gene therapy.

Cardiovascular gene therapy has been hampered by the lack of suitable gene delivery vectors for in vivo applications. Low transduction efficiencies, lack of persistent transgene expression and undesirable inflammatory and immune responses have limited the prospects for human gene therapy in the cardiovascular system. New prospects for cardiovascular gene therapy are a result of recent vector developments, in particular with the use of adeno-associated virus (AAV) based vectors in the heart and peripheral vasculature.

Acceleration of cheese ripening.

The characteristic aroma, flavour and texture of cheese develop during ripening of the cheese curd through the action of numerous enzymes derived from the cheese milk, the coagulant, starter and non-starter bacteria. Ripening is a slow and consequently an expensive process that is not fully predictable or controllable. Consequently, there are economic and possibly technological incentives to accelerate ripening. The principal methods by which this may be achieved are: an elevated ripening temperature, modified starters, exogenous enzymes and cheese slurries. The advantages, limitations, technical feasibility and commercial potential of these methods are discussed and compared.

Chemical structures of the core region of Campylobacter jejuni O:3 lipopolysaccharide and an associated polysaccharide.

The complete structure for the core oligosaccharide region of the water-insoluble low-M(r) lipopolysaccharide of Campylobacter jejuni serotype O:3 from phenol/water extraction of bacterial cells was assigned through studies on derivatives of the liberated oligosaccharide. Structure determinations were performed using 1H-NMR and 31P-NMR spectroscopies, methylation analysis supported by fast-atom-bombardment mass spectrometry, and Smith degradation experiments. It was concluded that the complete chains in the core oligosaccharide had the following structure in which a proportion of the terminal residues were phosphorylated: [formula: see text] From a similar series of experiments, it was concluded that an associated polysaccharide, which was isolated from the water phase of the phenol/water extracts, had the following repeating unit in which a proportion of the previously unknown L-glycero-D-ido-heptose (L-alpha-D-ido-Hep) residues were present as 3-hydroxypropanoyl esters, and were not covalently linked to the lipopolysaccharide: [formula see: text]