Demographic scope and economic magnitude of contemporary organ replacement therapies.

This analysis draws upon a variety of sources to provide a tally of the number of patients receiving organ replacement therapies and the costs associated with the provision of such therapies. Constituent data were available from treatment-specific patient registries, peer reviewed reports in scientific literature, business publications, and industry sources. The magnitude and economic scope of the contemporary organ replacement enterprise were found to be much larger than is generally recognized. In the year 2000, the lives of over 20 million patients will be sustained, supported, or significantly improved by functional organ replacement. The impacted population grows at over 10% per year. Worldwide, first year and follow-up costs of organ prosthesis exceeds $300 billion US dollars per year and represents between 7 and 8% of total worldwide health care spending. Remarkably, in the United States, the costs of therapies enabled by organ replacement technology exceed 1% of the Gross Domestic Product. These findings constitute an incontestable tribute to the scientific significance and medical impact of the still nascent field of substitutive medicine. At the same time, the enormous magnitude of resources dedicated to organ replacement raises several issues related to overall cost effectiveness of current modalities and raises challenges and opportunities for future technical developments.

Identification of novel pro-alpha2(IX) collagen gene mutations in two families with distinctive oligo-epiphyseal forms of multiple epiphyseal dysplasia.

Multiple epiphyseal dysplasia (MED) is a genetically heterogeneous disorder with marked clinical and radiographic variability. Traditionally, the mild "Ribbing" and severe "Fairbank" types have been used to define a broad phenotypic spectrum. Mutations in the gene encoding cartilage oligomeric-matrix protein have been shown to result in several types of MED, whereas mutations in the gene encoding the alpha2 chain of type IX collagen (COL9A2) have so far been found only in two families with the Fairbank type of MED. Type IX collagen is a heterotrimer of pro-alpha chains derived from three distinct genes-COL9A1, COL9A2, and COL9A3. In this article, we describe two families with distinctive oligo-epiphyseal forms of MED, which are heterozygous for different mutations in the COL9A2 exon 3/intron 3 splice-donor site. Both of these mutations result in the skipping of exon 3 from COL9A2 mRNA, but the position of the mutation in the splice-donor site determines the stability of the mRNA produced from the mutant COL9A2 allele.

Impact of metronidazole therapy on preterm birth in women with bacterial vaginosis flora (Gardnerella vaginalis): a randomised, placebo controlled trial.

OBJECTIVE: To ascertain whether metronidazole treatment of women with a heavy growth of Gardnerella vaginalis during mid-pregnancy would reduce the risk of spontaneous preterm birth. DESIGN: A multicentre, randomised, placebo-controlled trial. SETTING: Four metropolitan hospitals. PARTICIPANTS: Eight hundred and seventy-nine singleton women with a heavy growth of G. vaginalis or Gram stain indicative of bacterial vaginosis at 19 weeks of gestation. INTERVENTIONS: Oral metronidazole (400 mg) or placebo twice daily for two days at 24 weeks of gestation, and at 29 weeks if G. vaginalis found in test-of-cure swab four weeks after treatment. MAIN OUTCOME MEASURES: Spontaneous preterm birth less than 37 weeks. RESULTS: Intention-to-treat analysis showed no difference between metronidazole and placebo groups in overall preterm birth (31/429 [7.2%] vs 32/428 [7.5%]) or spontaneous preterm birth (20/429 [4.7%] vs 24/428 [5.6%]). Among the 480 women with bacterial vaginosis treatment had no effect on spontaneous preterm birth (11/242 [4.5%] vs 15/238 [6.3%]). In the subset of 46 women with a previous preterm birth, women in the metronidazole group showed a significant reduction in spontaneous preterm birth (2/22 [9.1%] vs 10/24 [41.7%], OR 0.14, 95% CI 0.01-0.84). A treatment effect was also found in compliant women with a previous preterm birth and bacterial vaginosis (0/14 [0%] vs 6/17 [35.3%], OR 0.0, 95% CI 0.0-0.94). CONCLUSION: Metronidazole treatment of women with a heavy growth of G. vaginalis or bacterial vaginosis did not reduce the preterm birth rate. Among women with a previous preterm birth, treatment reduced the risk of spontaneous preterm birth. Further studies are required to confirm these findings.

Prevention of early onset group B streptococcal sepsis in the newborn.

There is an urgent need for strategies to prevent early onset group B streptococcal sepsis in the newborn. The most effective mechanism is the identification of maternal carriers of the organism and interruption of transmission during labour. Vaginal culture is currently the most reliable method for the identification of carriers. Antibiotic prophylaxis for known carriers in labour has been demonstrated to be effective as standard management practice in a number of Australian institutions and is the best available strategy at this stage.

Genetic mapping of a locus for multiple epiphyseal dysplasia (EDM2) to a region of chromosome 1 containing a type IX collagen gene.

Multiple epiphyseal dysplasia (MED) is a dominantly inherited chondrodysplasia characterized by mild short stature and early-onset osteoarthrosis. Some forms of MED clinically resemble another chondrodysplasia phenotype, the mild form of pseudoachondroplasia (PSACH). On the basis of their clinical similarities as well as similar ultrastructural and biochemical features in cartilage from some patients, it has been proposed that MED and PSACH belong to a single bone-dysplasia family. Recently, both mild and severe PSACH as well as a form of MED have been linked to the same interval on chromosome 19, suggesting that they may be allelic disorders. Linkage studies with the chromosome 19 markers were carried out in a large family with MED and excluded the previously identified interval. Using this family, we have identified an MED locus on the short arm of chromosome 1, in a region containing the gene (COL9A2) that encodes the alpha 2 chain of type IX collagen, a structural component of the cartilage extracellular matrix.

Bacterial vaginosis in pregnancy and efficacy of short-course oral metronidazole treatment: a randomized controlled trial.

OBJECTIVE: To characterize the natural history of bacterial vaginosis in pregnancy and to assess the efficacy of short courses of oral metronidazole therapy for long-term suppression of bacterial vaginosis flora. METHODS: This was a randomized, double-blind, placebo-controlled study of two 2-day courses of metronidazole (400 mg twice daily) in pregnant women with bacterial vaginosis (by Gram stain) and/or heavy growth of Gardnerella vaginalis. The first course was given at 24 weeks' gestation and a second course at 29 weeks if the follow-up vaginal swab grew G vaginalis. Follow-up swabs were performed at 28, 32, and 36 weeks' gestation. RESULTS: On the basis of their G vaginalis colonization, 196 women were enrolled, and 137 were evaluable for efficacy, including 66 with bacterial vaginosis. The microbial ecology of bacterial vaginosis in 36 women in the placebo group was relatively stable, with 72% persistence at 28 weeks and 57% at 32 weeks' gestation. Metronidazole effectively suppressed bacterial vaginosis for 4 weeks after the first course in 76%, compared with 28% in the placebo group, and had a cumulative efficacy of 87% compared to 44% 4 weeks after the second course (odds ratio 0.12, 95% confidence interval 0.03-0.5). CONCLUSIONS: The microbial ecology of bacterial vaginosis in pregnant women is relatively stable. Long-term suppression of bacterial vaginosis flora for 2-3 months can be achieved by short courses of metronidazole therapy in 87% of women in mid-pregnancy. Because bacterial vaginosis has been associated with an increased risk of preterm labor, these findings provide the foundation for an intervention study of women with bacterial vaginosis in pregnancy.

Changes in vaginal flora during pregnancy and association with preterm birth.

A prospective study of the vaginal flora changes between midtrimester and labor was undertaken in 560 women; 337 had intact membranes and were in labor when swabs were taken. Of these, 45 delivered preterm. Gardnerella vaginalis, Ureaplasma urealyticum (both associated with preterm birth when present in midtrimester), and Mycoplasma hominis commonly persisted between midtrimester and labor, particularly in the preterm cohort (24 [65%] of 37 midtrimester isolates), and these organisms were seldom acquired late in pregnancy. A second group, Bacteroides species, had both a high persistence (9 [60%] of 15 midtrimester isolates) and high late acquisition rate (10 [53%] of 19 labor isolates) in the preterm cohort. These findings provide a rationale for treatment of bacterial vaginosis in pregnancy. A third group, comprising enteropharyngeal bacteria and Peptostreptococcus species, were almost all acquired late in the preterm cohort (14 [88%] of 16 labor isolates), and persistence from midtrimester was rare.

Mutation screening by a combination of biotin-SSCP and direct sequencing.

We have developed a mutation detection strategy that combines single strand conformational polymorphism (SSCP) analysis of one strand of a double-stranded amplification product with direct sequencing of the other. Using this strategy, which we find economical of both time and resources, we have identified a G to A transition, which substitutes a serine for glycine residue at position 862 in the major helix of the alpha 1 chain of Type I collagen. We use this mutation, which causes a lethal form of osteogenesis imperfecta, to illustrate the technique.

Sexuality and pregnancy. An interview study.

This paper reports the interview research which formed the basis for a large recently completed study of sexuality and pregnancy by questionnaire. Semistructured interviews were conducted with 25 couples who presented at a large hospital antenatal clinic in the first trimester. Of these couples, 15 participated in second trimester interviews and 12 couples were interviewed between 38 and 40 weeks' gestation. The results showed a substantial decline in sexual interest amongst women that was not matched by their male partners but was reflected in a marked reduction in frequency of intercourse. The range of sexual activities also diminished during pregnancy. The majority (19 or 76%) regularly practised oral sex and 3 men (12%) regularly practised anal intercourse. A key observation is that 7 males (28%) did not always achieve orgasm during sexual intercourse per se.

Prenatal microbiological risk factors associated with preterm birth.

OBJECTIVE: To study the vaginal flora of pregnant women at 22-28 weeks gestation to determine whether the presence of specific micro-organisms is significantly associated with preterm birth and prelabour rupture of the membranes. DESIGN: A comprehensive descriptive prospective study of the vaginal micro-flora of women between 22-28 weeks gestation comparing those who gave birth preterm (less than 37 weeks) with those who gave birth at term. Microbiological assessment included cultures for aerobic and anaerobic bacteria, yeasts, genital mycoplasmas and Trichomonas vaginalis. Multiple logistic regression analysis was used to account for confounding obstetric and demographic variables. SETTING: The Queen Victoria Hospital, Adelaide, South Australia. SUBJECTS: 135 women who gave birth preterm compared to 651 women who gave birth at term. MAIN OUTCOME MEASURE: Preterm birth and preterm prelabour rupture of membranes (PROM) RESULTS: The prevalence of Gardnerella vaginalis between 22-28 weeks was significantly higher in women who gave birth preterm compared to women who gave birth at term (23% vs 15%; multiple logistic regression odds ratio (OR) 1.8, 95% confidence intervals (CI) 1.01-3.2, P less than 0.05. Ureaplasma urealyticum was also found in a higher proportion of women who gave birth preterm (49% vs 32% OR 1.7, 95% CI 1.1-2.6, P less than 0.0005). Preterm PROM occurred in 42% of whom 60% were carriers of U. urealyticum between 22-28 weeks, compared with 32% in the term group (OR 3.2, CI 1.7-6.1, P less than 0.0005). When women who received antibiotics between the midtrimester swab and labour were excluded, G. vaginalis was also significantly associated with preterm PROM (OR 2.7, CI 1.1-6.5, P less than 0.05). The presence of vaginal enteropharyngeal bacteria (E. coli, Klebsiella spp., Haemophilus spp., Staph. aureus) in the midtrimester was not predictive of preterm birth, but when these organisms were found in labour, they appeared to have been acquired later in the pregnancy. CONCLUSION: Women carrying G. vaginalis or U. urealyticum during the midtrimester had nearly twice the risk of preterm birth, while women positive for U. urealyticum had more than a threefold risk of preterm PROM.

Vaginal infection and preterm labour.

OBJECTIVE: To study the vaginal flora of women in preterm labour (PTL) and determine whether the presence of specific vaginal microflora is significantly associated with onset of PTL. DESIGN: A comprehensive prospective study of the vaginal microflora of women in early labour comparing women in PTL with term controls. Microbiological assessment included cultures for aerobic and anaerobic bacteria, yeasts, genital mycoplasmas and Trichomonas vaginalis. Multiple logistic regression analysis was used to adjust for confounding obstetric and demographic variables. SETTING: The Queen Victoria Hospital, Adelaide. PATIENTS: 428 Women in PTL compared to 568 women in labour at term. MAIN OUTCOME MEASURE: PTL and preterm prelabour rupture of membranes (PPROM) in relation to specific vaginal microflora. RESULTS: After multiple logistic regression analysis, two distinct bacteriological groupings were associated with PTL less than 37 weeks gestation, namely, the bacterial vaginosis group of organisms, Gardnerella vaginalis and Bacteroides spp., and a group of enteropharyngeal organisms, E. coli, Klebsiella spp., Haemophilus spp. and S. aureus. G. vaginalis was found in 12% of women in PTL compared to 6% at term [regression odds ratio (ROR) 1.8, 95% confidence intervals (CI) 1.1-3.1] whereas Bacteroides spp. were detected in 45% of women in PTL compared with 35% at term (ROR 1.6, CI 1.2-2.1). The prevalence of G. vaginalis (17%) and Bacteroides spp. (50%) was even higher in women in PTL less than 34 weeks gestation. The enteropharyngeal group of organisms were more commonly present in women in PTL less than 37 weeks (E. coli 10% vs 6%, ROR 1.4, CI 0.8-2.4; Klebsiella spp. 3% vs less than 1%, ROR 5.4, CI 1.1-26.7; Haemophilus spp. 2% vs less than 1%, ROR 5.5, CI 1.1-28.6; S. aureus 6% vs 4%, ROR 1.8, CI 0.9-3.3) and were isolated even more frequently in women in PTL less than 34 weeks (E. coli 15%; Klebsiella spp. 4%; S. aureus 7%). Bacteroides spp., Klebsiella spp., and Haemophilus spp. were all found to be associated with PPROM. CONCLUSION: There are two distinct bacteriological groupings commonly found in women in PTL, especially in PTL less than 34 weeks gestation. These bacteriological groups are women with bacterial vaginosis in pregnancy and women who demonstrate enteropharyngeal bacteria in the vagina.

Group B streptococcal colonization and preterm labour.

Recent publications have highlighted the controversy regarding the significance of Lancefield Group B Streptococcal (GBS) colonization in pregnancy and preterm delivery. In this prospective study vaginal swabs from 692 women at approximately 24 weeks' gestation were cultured for GBS. GBS was detected in 91 (13.2%) women. The rate of preterm labour (PTL) (less than 37 weeks) was significantly higher in GBS positive women than in GBS negative women (18.7% versus 5.5%; p less than 0.001). This association remained significant even when patients with other recognized factors predisposing to PTL were excluded (11.5% versus 3.9%; p less than 0.001). The rate of premature rupture of membranes (PROM) was also significantly higher in GBS positive women (9.9% versus 2.7%; p less than 0.005) and remained significantly higher when patients with other recognized risk factors were excluded (6.1% versus 1.8%; p less than 0.025). These results unequivocably show that pregnant women who are vaginal carriers of GBS have a significantly increased risk of PROM and PTL.

Fetal renal vein thrombosis.

Two cases of fetal renal vein thrombosis, diagnosed via maternal ultrasound scan are presented. One was associated with severe placental dysfunction and demonstrated haematuria and renal failure which resolved on day 10. The other followed an antepartum haemorrhage and resolved before the baby was born. The ultrasound showed, as transient findings, unilateral renal enlargement, thrombus protruding into the inferior vena cava, and mild fetal ascites. We suggest that fetal renal vein thrombosis may be more common than previously suspected, and warrants close monitoring of fetal well-being. Delivery should be considered if there is other evidence of fetal compromise, if the amount of peritoneal fluid suggests substantial haemorrhage, or if there is propagating thrombus in the inferior vena cava.