Virtual learning using interactive multimedia-based tools for knowledge transfer and development of global patient care pathway in haemoglobinopathies.

Hemoglobinopathies are the most common global monogenic disorders with significant mortality and morbidity of the survivors. This is due to poor understanding of the disease(s) by health care professionals and also lack of resources. We have designed a Master's degree in hemoglobinopathies course, the first of its kind, using cutting-edge lively state-of the-art media-based technology, to attain excellence in teaching and learning. The modular program is delivered by 100% virtual learning (VLE) tools. The lectures, given by international experts, are blended with interactive quizzes and assessment tools to make the program engaging. Other activities include video-based tutorials, walk-in surgeries, journal clubs and other web-based activities. We have currently received 40 intakes and the program is running successfully with excellent student feedback using quality control framework of the University College London (UCL), London, UK. In conclusion, we have shown the feasibility of VLE for knowledge and skill transfer to global healthcare professionals for a monogenic disorder.

Urinary inositol phosphoglycan P-type as a marker for prediction of preeclampsia and novel implications for the pathophysiology of this disorder.

OBJECTIVE: Hypertensive disorders represent the most common complications of human pregnancy with substantial impact on fetal and maternal outcomes. Inositol phosphoglycan P-type has recently been identified as a novel marker of preeclampsia, the most severe form of hypertension during pregnancy, with a significant increase in urinary excretion preceding the clinical diagnosis. METHODS: A prospective, longitudinal study was carried out to assess the potential of urinary levels of inositol phosphoglycan P-type as a screening test for preeclampsia. A specific ELISA-based test was used to assess urinary levels of P-IPG. RESULTS: Nine patients out of 93 women recruited (496 urinary samples were collected) went on to develop preeclampsia in a cohort of women with high-risk pregnancies. A cut-off value of urinary inositol phosphoglycan P-type was identified by ROC analysis providing a sensitivity and specificity for the current protocol of 88.9% and 62.7%, respectively. Twenty-three women with healthy pregnancies had sporadic episodes of increased excretion of inositol phosphoglycan P-type during pregnancy that consistently resolved back to normal baseline without development of preeclampsia. There was no correlation of urine levels of inositol phosphoglycan P-type and urine protein and patients with gestational hypertension had normal levels of urine inositol phosphoglycan P-type. CONCLUSIONS: These findings suggest that, given the rapid raise of P-IPG before the onset of the disease, multiple assessments may help at identifying women at risk of developing preeclampsia.

Maternal insulin-like growth factors 1 and 2 (IGF-1, IGF-2) and IGF BP-3 and the hypertensive disorders of pregnancy.

OBJECTIVE: To investigate the relationship between levels of insulin-like growth factors 1 and 2 (IGF-1, IGF-2) and insulin-like growth factor binding protein 3 (IGFBP-3) in antenatal maternal serum and gestational hypertension and pre-eclampsia (PET). METHODS: Prospective cohort study of 1650 low-risk Caucasian women in a University teaching hospital in London. Statistical analysis was performed using commercial software (SPSS for Windows, version 6.1, SPSS, Chicago, IL), with P < 0.05 as significant. Maternal IGF 1, IGF 2 and IGF BP-3 were assessed on maternal blood at booking. Blood pressure was checked at each visit in conjunction with urine analysis. The Davey & MacGillivray 1988 classification system was used in making the diagnosis of PET. RESULTS: There was no significant correlation between maternal IGF-1 or IGFBP-3 levels and gestational hypertension or PET. However, a significant positive correlation does exist between maternal IGF-2 levels and PET. CONCLUSIONS: Maternal IGF-2 has a significant positive correlation with PET.

Ultrasonographic development of the fetal sheep stomach and evaluation of early gestation ultrasound-guided in utero intragastric injection.

OBJECTIVE: Safely targeting the fetal gastrointestinal tract during early gestation is essential to develop effective prenatal gene therapy for gastrointestinal diseases. In this study, we aimed to characterize the development of the fetal sheep stomach sonographically and to determine the optimum gestational age, as well as the shortterm morbidity and mortality of early-gestation ultrasound-guided intragastric injection. MATERIALS AND METHODS: In experiments investigating ultrasound-guided prenatal gene therapy, we studied the size and development of the stomach of 185 sheep fetuses (33-144 days' gestational age [GA]; term is 145 days). Ultrasound-guided intragastric injection was performed in 12 fetuses at 55-62 days' GA and postmortem examinations were performed 48 hours later. RESULTS: The stomach was not visible at or before 40 days' GA, but it was seen in all fetuses at 55 days' GA or more. The anteroposterior, transverse and longitudinal diameters of the stomach increased in a quasi-linear fashion throughout gestation. Intragastric injection was successful in 10 out of the 11 fetuses (91%) injected at 60-62 days' GA, with nine fetuses (91%) surviving this procedure. CONCLUSION: In the early-gestation sheep fetus, ultrasound-guided intragastric injection has a good success rate with a low short-term mortality and morbidity.

The relationship between maternal insulin-like growth factors 1 and 2 (IGF-1, IGF-2) and IGFBP-3 to gestational age and preterm delivery.

AIMS: To investigate the relationship between levels of insulin-like growth factors 1 and 2 (IGF-1, IGF-2), and insulin-like growth factor binding protein 3 (IGFBP-3) in antenatal maternal serum and gestational age at delivery. METHODS: Prospective cohort study of 1650 low-risk Caucasian women in a London University teaching hospital. Maternal IGF-1, IGF-2 and IGFBP-3 were measured in maternal blood at booking and analyzed with respect to gestational age at delivery. RESULTS: There was no significant association between maternal IGF-1 or IGF-2 and preterm birth (PTB). A significant reduction in mean IGFBP-3 levels was noted with delivery <32 completed weeks (P=0.02). CONCLUSION: Maternal mean IGFBP-3 levels are significantly reduced in cases complicated by delivery <32 completed weeks.

Increased inositol phosphoglycan P-type in the second trimester in pregnant women with type 2 and gestational diabetes mellitus.

A progressive insulin resistant state develops throughout human pregnancy. Inositol phosphoglycan P-type (P-IPG), a second messenger of insulin, was reported to negatively correlate with the degree of insulin resistance in non-pregnant diabetic subjects. Urinary levels of P-IPG were assessed in insulin resistant states during pregnancy such as gestational diabetes mellitus (GDM, n=44) and type 2 diabetes mellitus (type 2 DM, n=25) and in 69 normal pregnant women. Urinary levels of P-IPG were higher in GDM than controls with a positive trend of release throughout normal pregnancy (P<0.01). P-IPG excretion was higher in diabetic (GDM and type 2 DM) than in healthy women in the second trimester (P<0.05). A higher P-IPG urinary excretion occurs during the second trimester in pregnant women with clinically evident insulin resistance with a positive association with poor glycemic control.

Placental calcification in pseudoxanthoma elasticum.

INTRODUCTION: Pseudoxanthoma elasticum (PXE) is an inherited multisystem disorder of the elastic tissue and the objective of this case report is to correlate ultrasonographic and histological appearances of placental calcification in PXE. CLINICAL PICTURE: We report a case of a 37-year-old white woman with PXE, whose antenatal imaging showed a markedly echogenic placenta due to extensive calcification confirmed on postpartum placental histology. OUTCOME: There were no maternal or fetal complications in the antenatal period. A healthy baby of appropriate maturity and weight was delivered via Caesarean section and remained well at 6 months. CONCLUSION: The majority of cases of PXE is caused by mutations in the ABCC6 gene. Serious complications in pregnancy can include gastrointestinal haemorrhage, congestive heart failure and cardiac arrhythmia but has not been shown to be associated with markedly increased fetal loss or adverse reproductive outcomes as reported in previous literature. Apart from the cosmetic deterioration of the abdominal skin, there were few serious complications and most have normal pregnancies. Obstetric prognosis is dependent on the vascular damage caused by the illness. There is no basis for advising women with PXE to avoid becoming pregnant, and most pregnancies in PXE are uncomplicated.

Release of inositol phosphoglycan P-type by the human placenta following insulin stimulus: a multiple comparison between preeclampsia, intrauterine growth restriction, and gestational hypertension.

OBJECTIVE: Abnormal metabolism of inositol phosphoglycan P-type (P-IPG) has been described in insulin-resistant states. Recently, a definite link between P-IPG and preeclampsia has been reported. P-IPG release after insulin stimulus has been described in the placental tissue of healthy women and a complete absence of P-IPG release has been found in preeclamptic samples, associated with disturbed insulin signaling. This study was undertaken to assess the release of this mediator in intrauterine growth restriction (IUGR) and hypertensive disorders other than preeclampsia. METHODS: Seven women with IUGR, seven with gestational hypertension, 11 with preeclampsia, and 12 controls were recruited for this study. Fresh placental membranes were prepared and incubated with human recombinant insulin. Bioactivity of P-IPG released after insulin stimulus was assessed using a specific bioassay. A multiple comparison between groups was carried out. The study population provided a statistical power of 0.94. RESULTS: P-IPG release was highest and lowest from healthy and preeclamptic samples, respectively (p < 0.01). Specimens from patients with IUGR and gestational hypertension released less P-IPG than did controls (p < 0.05). CONCLUSIONS: Abnormal release of P-IPG from placentas of IUGR and gestational hypertensive mothers seems to confirm an association between these disorders of human pregnancy and insulin resistance.

Gender, smoking during pregnancy and gestational age influence cord leptin concentrations in newborn infants.

BACKGROUND: Low birth weight (BW), small head circumference, reduced length, increased preterm births and neuro-endocrine dysfunctions are among known consequences of smoking during pregnancy. Few studies have linked leptin to clinical features of growth restriction associated with maternal smoking and explored interaction with other determinants of size at birth, such as gender. METHODS: Cord serum leptin concentrations were measured in 1215 term infants born to Caucasian mothers at completion of uneventful pregnancy. Serum concentrations were related to BW, gestational length, gender and maternal smoking and interaction with other determinants of size at birth evaluated. RESULTS: Smoking was more frequent in younger (P<0.001) and shorter mothers (P=0.03) from lower socio-economic groups (SEGPs) (P<0.001). Infants born to smokers were lighter (190 g less), shorter and with smaller head circumference. Cord serum leptin concentrations were higher in girls (9.8 s.d. 7.6 ng/ml) than in boys (7.05 s.d. 5.8 ng/ml) (P<0.001). Boys were heavier (BW 3.52 s.d. 0.49 kg) than girls (3.39 s.d. 0.44 kg) (P<0.001), but girls had greater skinfold thickness measurements (sub-scapular and quadriceps skinfold thicknesses 5.5 s.d. 1.6 mm and 7.6 s.d. 1.9 mm respectively; boys 5.3 s.d. 1.6 vs 7.24+/-1.90 mm, P<0.001 respectively). Multivariate analyses showed gender (P<0.001), BW SDS (P<0.001), gestational length (P<0.001) and maternal smoking (P<0.042) as factors that influenced umbilical cord serum leptin concentrations in newborns. CONCLUSION: Maternal smoking restrains foetal growth through placental vascular effects, and likely also via associated effects on leptin metabolism. More studies are needed to determine the influence that maternal smoking may have on placental syncytiotrophoblast and foetal adipose tissue.

Feasibility of dynamic 3-D color Doppler ultrasound for imaging penile vascular change in renal transplant patients with erectile dysfunction responding to sildenafil.

Renal transplant recipients (RTRs) have a high incidence of erectile dysfunction (ED). Differentiation of penile vasculogenic impotence from other causes is important for treatment. Conventional 2-D color Doppler assessment after intracavernosal stimulant injection often fails to produce reliable results because of limited views by the cross-sectional imaging and the painful procedure. In comparison to the findings in three healthy volunteers, we determined cavernosal vascular hemodynamics in eight RTRs with ED before and after oral sildenafil by using live 3-D ultrasound and dynamic 3-D color Doppler. Results showed that, before sildenafil, penile arterial flow signals could only be reliably detected in one patient. After sildenafil, all had reliably detectable flow with grades II to III erection. Our data suggest that 3-D volumetric changes of the penis and its vasculature during erection can be studied by this technique and that this method could be useful for the evaluation of new drugs and therapeutic biofeedback.

Ethical considerations of fetal therapy.

Fetal therapy raises ethical concerns in relation to the balance of potential benefit and harm, autonomy and informed consent, and the duties of the clinician to the pregnant women and fetus. Invasive therapy should be recommended only when it has a realistic chance of saving the life of the fetus and offspring or preventing serious and irreversible disease or disability. Clinicians should respect maternal choice and assessment of risk, particularly if the therapy might be only partially successful, leaving the offspring with a profound morbidity. Fetal therapy should not be undertaken without maternal consent; nor should it be presented coercively as an option to avoid a termination of pregnancy. Therapeutic procedures of unproven efficacy should be undertaken only with the voluntary informed consent of the pregnant woman and according to a clearly defined research protocol that has been approved by an appropriate research ethics committee and where appropriate support and counselling can be provided.

Factors predicting ante- and postnatal growth.

Human growth is a continuous process. Studies defining factors influencing growth focus on discrete time points (e.g., birth), overlooking the conditional nature of the process. One thousand six hundred fifty Caucasian mothers who gave birth at term after an uncomplicated singleton pregnancy were studied using conditional analysis. Infant height, weight, and head circumference were obtained at birth and 6 mo of age. Data analysis, conditional upon birth size, was conducted as a stepped consideration of factors influencing phases of fetal and infant growth beginning with determinants of placental size. Placental weight was related to birth size. Seven percent of the variance in placental weight was explained by a combination of gestation at delivery, maternal size at first prenatal visit, paternal height (all positive), and increasing parity (negative). When centered on birth weight, 41% of the variance in placental weight was explained by birth weight, length of gestation, smoking during pregnancy (all positive), and a female baby (negative). Maternal and paternal stature equally influenced newborn and infant size. Conditional analysis reveals a series of modifiable (parity, length of gestation, and smoking) and nonmodifiable factors at different stages of the growth process.

Fetal gene transfer.

Gene transfer early in development for the treatment of monogenetic and other diseases could overcome major obstacles of intervention in the mature individual. Early gene transfer may prevent the onset of irreversible pathological changes, predispose the individual to immunological tolerance to the introduced protein, take advantage of the high vector to cell ratio, and provide unique access to stem cell/progenitor compartments. The past few years have witnessed the publication of five studies showing long-term correction of monogenetic disorders by fetal gene transfer. Many others have examined the use of new vector systems with therapeutic transgenes, tested their potential for treating diseases in a wide range of organs (including the brain, lung and skin), and examined the hazards of fetal application. This review gives a comprehensive summary of the development of fetal gene transfer over the past few years.

Altered urinary release of inositol phosphoglycan A-type in women with gestational diabetes mellitus.

BACKGROUND/AIMS: The mechanisms underlying overgrowth of adipose tissue in fetuses of women with gestational diabetes mellitus (GDM) are generally unknown. Inositol phosphoglycan A-type (A-IPG), a putative second messenger of insulin, was reported to regulate lipogenesis in adipose tissue. IPGs have recently been shown to increase during normal pregnancy, in maternal and fetal compartments. METHODS: 48 women with GDM and 23 healthy pregnant women were recruited for this cross-sectional study. Levels of A-IPG were assessed enzymatically in urinary specimens and correlated with clinical parameters. RESULTS: A-IPG urinary release was lower in GDM patients (p < 0.01) and correlated positively with BMI (p < 0.01) and negatively with glycaemic control in the diabetic group (postprandial glycaemia and glycated haemoglobin, p < 0.01) in addition to a nearly significant correlation with birth weight (p = 0.08). Furthermore, a lower A-IPG urinary release was found in diabetic subjects with normal fasting glycaemia compared with those with poor fasting glycaemic control (p < 0.05). CONCLUSIONS: An altered A-IPG urinary excretion occurs in GDM with a negative correlation with poor glycaemic control. Our data suggest an interesting potential role of this molecule in maternal metabolic control during pregnancy and, possibly, in fetal growth.

Inositol phosphoglycan P-type in healthy and preeclamptic pregnancies.

An association between inositol phosphoglycan P-type (P-IPG) and preeclampsia has been demonstrated over recent years. This molecule can mediate many of the metabolic and growth promoting effects of insulin. Dysregulation of the mediator family is associated with insulin resistance. An increased concentration of P-IPG has been reported in preeclamptic placenta, although its precursor (GPI) was undetectable in those placental samples. Insulin administration, that induces P-IPG release in normal human placenta, was shown not to cause production/release of the mediator from preeclamptic placental tissue as a consequence of a disturbed insulin signalling. Amniotic fluid is enriched of this mediator, with further increase during preeclampsia. We have found that the fetus released increasing amounts of P-IPG in the urine between 13 and 18 weeks of gestation, reaching a plateau beyond 20 weeks. Cord blood of infants of preeclamptic mothers showed an increased content of soluble P-IPG compared to controls and to the mother.

Ultrasound findings after screening for Down syndrome using the integrated test.

OBJECTIVE: To evaluate the incidence and significance of fetal anomalies and "soft markers" after screening for Down syndrome using the integrated test. METHODS: This study is a retrospective study of 2,332 women at University College London Hospitals, United Kingdom. All women were screened for Down syndrome by the integrated test. Subsequently, a detailed anomaly scan was performed. All scan reports and screening results were analyzed statistically using SPSS 11.0 software. RESULTS: Sixty-eight (2.9%) patients were categorized as high risk. There were 12 cases affected by Down syndrome, 10 (10 of 68) in the high-risk group and two (two of 2,264) in the low-risk group. Soft markers or structural anomalies were found in 13.0% of the low-risk group, in 29.4% of the high-risk group, and in 50% of the fetuses affected by Down syndrome. Multiplying the likelihood ratio of each marker with the risk of Down syndrome from the integrated test reduced the false-positive rate of the integrated test from 2.5% to 1.8%, but was accompanied by a reduction in the detection rate from 83% to 75%. CONCLUSION: Absence of structural anomalies or markers should not prevent offering karyotyping to women in the high-risk group, because this would result in a significant reduction in the detection rate of Down syndrome. Women screened as low risk by the integrated test who have isolated soft markers should not be offered an amniocentesis.

Minimally-compressive, three- and four-dimensional ultrasound imaging of the clitoris: a feasibility study.

There has been no objective means for imaging the three-dimensional (3D) morphology of the clitoris-a poorly understood, complex structure. A Live 3D ultrasound system with a matrix-array transducer was used for data acquisition from eight women. The transducer was positioned in front of and about 3 cm away from the clitoris, with a gel pad or water pad being placed in between. The pads allowed the delicate structures to be imaged without noticeable deformation. Quality images could be obtained with use of a water pad in all patients. The imaging volume was big enough to cover the clitoral glans and body simultaneously, allowing real-time 3D visualisation. To cover the entire clitoris, the probe was moved from one side of the crus to the other, or a four subvolume scan was performed. 3D clitoral anatomy was depicted from 71% of 51 water pad data-sets. The study demonstrates the feasibility of obtaining 3D clitoral ultrasound images. This will improve scientific and clinical understanding of the clitoral role in sexual activity. The minimally-compressive scanning offers an opportunity to visualise dynamic 3D (4D) morphology of other deformable body parts.

Sonographic diagnosis of SEDC and double heterozygote of SEDC and achondroplasia--a report of six pregnancies.

OBJECTIVE: To define the sonographic features of spondyloepiphyseal dysplasia congenita (SEDC) and the double heterozygote for SEDC and achondroplasia. METHODS: A retrospective review of 6 pregnancies in one family where one parent has achondroplasia and the other SEDC. RESULTS: There were 4 double heterozygote pregnancies and 2 where the fetus had SEDC. Shortening of long bones was evident in both conditions from around 16 weeks gestation. Other findings such as an increased nuchal translucency were more variable. CONCLUSIONS: Molecular analysis of the FGFR3 and COL2AI gene once mutations are known in a family such as reported here can inform prenatal diagnosis and help to distinguish between the double heterozygote and a fetus which has inherited a single mutation. The data presented here on the growth of the long bones and other sonographic features associated with SEDC may aid prenatal diagnosis in cases where the mutation is not known.

An update on antenatal screening for Down's syndrome and specific implications for assisted reproduction pregnancies.

Since the introduction of antenatal serum screening for Down's syndrome (DS) more than two decades ago, several screening approaches have been utilized in routine clinical practice. The current DS screening strategies involve mid-trimester serum biochemistry tests, first trimester tests combining sonographic markers and serum biochemistry and integration of first and second trimester markers. In this review, we evaluate the performance of DS screening strategies according to the Serum, Urine and Ultrasound Screening Study (SURUSS), the First and Second Trimester Evaluation of Risks (FASTER) Trial and the Serum Biochemistry and Fetal Nuchal Translucency Screening (BUN) Study. We also evaluate the performance of first trimester screening in studies and meta-analyses by other groups. Specific issues related to assisted reproduction technology (ART) pregnancies are also addressed in this review.

Hypothesis: the placental 'steal' phenomenon - a possible hazard of amnioreduction.

The twin-twin transfusion syndrome (TTTS) complicates approximately 15% of monochorionic twin pregnancies. Severe TTTS is associated with poor neonatal outcome and a relatively high rate of neurological abnormalities. Some studies have suggested this outcome to be more severe in cases treated by amnioreduction. In this paper we present a hypothesis that radical amnioreduction performed after 24 weeks of gestation might cause a shift of blood from the fetus into the placenta. This could explain some of the severe neurological outcomes, such as hypoxic ischemic brain damage, seen in these cases.