Iatrogenic secondary post‐partum haemorrhage: Apropos of two uncommon cases

In this article we would like to highlight uterine pseudoaneurysm as a cause of secondary post‐partum haemorrhage following Caesarean section. We would like to stress Doppler ultrasound scan as the initial screening modality for this condition. We also describe angioembolization as the prudent treatment option for this condition rather than resorting to surgery.     

Clinical pharmacology research in the pediatric patient: the challenge continues

For most of the 20th century, most drugs labeled by the United States Food and Drug Administration (USFDA) have not been adequately studied in the pediatric population. This lack of data has necessitated the continued dependence of practitioners on sub-optimal prescribing data placing pediatric patients at great risk of serious therapeutic misadventures. Recently, the USFDA has enacted and begun to enforce the Final Rule of 1997 which became effective on 1 April 1999. This rule is the culmination of the persistent efforts of numerous professional organizations, clinicians, academicians, the USFDA and others, to ensure the ready availability of appropriate data for medications intended for or that will be used in children. Unlike the 1994 Rule which voluntarily required pharmaceutical manufacturers to submit pediatric data, the Final Rule mandates submission of such data and, most importantly, empowers the USFDA to afford incentives and penalties for non-compliance including possible removal of already marketed products. This overview addresses many of the important components which must be included in the performance of a comprehensive clinical pharmacologic evaluation serving as the foundation for optimal dosing across the broad age range encompassing pediatric practice. Furthermore, the possible risk and/or benefits of the study must be reasonably defined prior to undertaking the study and clearly shared with the patient's caregivers. Consent should always be obtained from the caregiver and, when appropriate, assent obtained from the underage child. To facilitate such clinical investigations and to foster collaborative efforts with innovators and clinical research programs, the National Institutes of Health through the National Institute of Child Health and Human Development of the NIH established a network of Pediatric Pharmacology Research Units. These units have worked closely together and with other pediatric research centers to facilitate USFDA labeling of a number of commonly used medications. All of these very positive efforts highlight the many challenges that remain for the pediatric investigator and practitioner while underscoring the very positive environment in support of these efforts.     

Transepithelial paracellular leakiness induced by chronic phorbol ester exposure correlates with polyp-like foci and redistribution of protein kinase C-alpha

Although exposure of LLC-PK1 epithelial cell sheets to phorbol esters (TPA) causes a near immediate and total decrease of transepithelial electrical resistance (TER), continuation of exposure for 3 to 4 days results in a tachyphylactic response as TER begins to return to control levels. Recovery of TER is maximal by 5 to 6 days, but reaches only 70 to 80% of control level. A reciprocal change in the transepithelial flux of D-mannitol indicates that the TER decrease is indicative of an increase in tight junction permeability. Exposure of cell sheets to TPA for several days also results in the appearance of multilayered polyp- like foci (PLFs) across the otherwise one cell layer thick cell sheets. The pattern of penetration of the electron dense dye, ruthenium red, from the apical surface, across the tight junction and into the lateral intercellular space indicates that the tight junctions of the cell sheet become uniformly leaky after acute exposure to TPA. However, when exposure is continued for several days, only the junctions of cells in the PLFs manifest leakiness. The decrease in TER following acute TPA exposure correlates with the translocation of protein kinase C-alpha (PKC alpha) into a membrane-associated compartment. With exposure of several days, only a trace of PKC alpha is visible by Western immunoblot, and this is in the membrane-associated compartment. Immunofluorescent microscopy indicates that the trace of PKC alpha seen in the Western immunoblots is ascribable distinctly to cells of the PLFs. Monolayer areas between PLFs show no discernible immunofluorescent signal. The data therefore indicate that tight junction barrier function may be restored in certain areas by the down regulation of PKC alpha from the membrane-associated compartment. Failure to down regulate may result in the paracellular leakiness and abnormal cell architecture of the PLFs. Possible implications of this model for in vivo epithelial tumor promotion are discussed.      

Sputum tumour necrosis factor-alpha and leukotriene concentrations in cystic fibrosis

It is postulated that a vigorous host inflammatory response in the cystic fibrosis lung contributes to lung injury. Tumour necrosis factor-alpha (TNF-alpha) may play a part in that process and in the generation of leukotrienes. Therefore, the relationships between sputum TNF-alpha, leukotriene concentration, and lung function abnormalities in 16 children with cystic fibrosis were investigated. Each subject provided sputum samples and performed spirometry. TNF-alpha was measured by enzyme linked immunosorbent assay; individual leukotrienes were separated using high performance liquid chromatography and quantified by radioimmunoassay. The geometric mean concentration of TNF-alpha was 129.7 pg/ml and 95% confidence interval 48.2 to 348.3. Mean (SEM) leukotriene B4 (LTB4) was 97.8 (22.9) pmol/g and total cysteinyl leukotrienes were 60.9 (14.8) pmol/g. Mean (SD) forced expiratory volume in one second (FEV1) of the group was 53 (15)% of predicted and forced vital capacity (FVC) was 65 (14)% of predicted. There was a significant positive correlation between TNF-alpha and both LTB4 and the total cysteinyl leukotriene sputum content. An inverse relationship existed between TNF-alpha and FEV1 and FVC. Moreover, a negative correlation was observed between sputum LTB4 and FEV1 and FVC. These results suggest that TNF-alpha and the leukotrienes may participate in the airways inflammation and airflow obstruction observed in cystic fibrosis subjects and support the hypothesis that TNF-alpha upregulates the 5-lipoxygenase pathway in vivo.     

A new amino acid mixture permits new approaches to the treatment of phenylketonuria

A new amino acid mixture for incorporation into medical foods for the treatment of hyperphenylalaninemia has been tested in a regular clinic. The mix is designed to be as unobtrusive as possible, consistent with good nutrition. After more than 1 year of trial as a beverage, we have shown that it is safe and well tolerated but that plasma phenylalanine is no better controlled than with some other products. The mix can be incorporated into a large number of different foods without affecting the taste. Occult monitoring of the quantity of medical foods purchased compared with the amounts reported to be consumed in diet histories provides an excellent way to monitor dietary compliance.     

Is an ultrasound assessment of gestational age at the first antenatal visit of value? A randomised clinical trial

OBJECTIVES: To assess the efficacy of an ultrasound scan at the first antenatal visit. DESIGN: Randomised clinical trial. SETTING: Women's and Children's tertiary level hospital, Adelaide, Australia. POPULATION: Six hundred and forty-eight women attending for their first antenatal visit at less than 17 weeks of gestation who had no previous ultrasound scan in the pregnancy, who were expected to give birth at the hospital, and for whom there was no indication for an ultrasound at their first visit. METHODS: Eligible consenting women were enrolled by telephone randomisation into either the ultrasound at first visit group, who had an ultrasound at the time of their first antenatal visit, or the control group in whom no ultrasound assessment was done at their first antenatal visit. Both groups of women completed a questionnaire at the end of the first visit on their feelings towards the pregnancy and anxiety levels. Data were collected on details of any ultrasound assessments, including the 18 to 20 weeks morphology scan, and pregnancy outcome. All primary analyses were on an intention-to-treat basis. MAIN OUTCOME MEASURES: The number of women who needed adjustment in dates of 10 days or more on the basis of their 18 to 20 weeks ultrasound morphology scan, who were booked for their morphology scan at sub-optimal gestations, who had a repeat of their maternal serum screening test, or who felt worried about their pregnancy at the end of the first antenatal visit. RESULTS: Fewer women (9%) in the ultrasound at first visit group needed adjustment of their expected date of delivery as a result of the 18 to 20 week ultrasound, compared with 18% of women in the control group (RR 0.52, 95% CI 0.34-0.79; P = 0.002). The number of women who had the 18 to 20 week ultrasound assessment timed suboptimally was similar to that in the control group (16% vs. 21%), as was the number of women who had a repeat blood sample taken for maternal serum screening (6% vs. 6%). Fewer women in the ultrasound at first visit group reported feeling worried about their pregnancy (RR 0.80, 95% CI 0.65-0.99; P = 0.04) or not feeling relaxed about their pregnancy (RR 0.73, 95% CI 0.56-0.96; P = 0.02), compared with women in the control group. CONCLUSIONS: A routine ultrasound assessment for dating offered to women at the first antenatal visit provides more precise estimates of gestational age and reduces the need to adjust the estimate of the date of delivery in mid-gestation. Women who had an ultrasound at the first visit reported more positive feelings about their pregnancy, compared with women in the control group at that time.     

A combined ultrasonic linear array scanner and pulsed Doppler velocimeter for the estimation of blood flow in the foetus and adult abdomen--I: Technical aspects

A method is proposed for estimating the volume blood flow of deep lying vessels in the foetus and in adult portal vein and renal vessels. The equipment combines a 3.5 MHz linear array scanner with a 2 or 4 MHz pulsed Doppler. The pulsed Doppler tranducer is connected to the linear array by two movable arms. A real time spectrum analyser is used to process the Doppler signals. A water bath was used to perform an in vitro calibration of the complete system and to adjust the registration of the Doppler sample volume with the echo picture. Several possible inaccuracies in vessel diameter measurement are discussed and the mean of several caliper measurements described by Eik-Ness (1982) is used. Time Motion is thought to be the better method but is more complicated in practice.     

Prevalence of deep venous thrombosis in the lower extremities of children in the intensive care unit

Purpose. To determine the prevalence of lower extremity deep venous thrombosis (LE-DVT) in children who spent at least 72 h in the pediatric intensive care unit (ICU). Materials and methods. Children up to the age of 17 years who spent at least 72 h in the ICU underwent lower extremity venous ultrasound at the end of their stay. Prevalence range for the sample size was calculated with a confidence interval of 95%. Results. Among 76 children who spent 3–141 days in the ICU, the prevalence of acute (and silent) DVT was 4 % (confidence interval 0–9 %). All three affected children had femoral venous catheters in that leg during their ICU stay (17 unaffected children also had catheters). Conclusion. Children in an ICU setting are at significantly lower risk for thrombosis than adults in the same setting.     

Metronidazole (Flagyl): characterization as a cytotoxic drug specific for hypoxic tumour cells.

The cytocidal properties of metronidazole against hypoxic mammalian cells are described. This chemotherapeutic action has been shown to be dependent on drug concentration and duration of exposure. The x-ray TCD50 for a murine anaplastic carcinoma was reduced from 6081 rad to 4643 rad when animals were given metronidazole orally for 36 h before radiation treatment. The effect is attributed to the direct killing of hypoxic tumour cells by a mechanism analogous to that proposed for the action of the drug on anaerobic micro-organisms. It is concluded that further work with metronidazole as a cytotoxin specific for hypoxic cells is warranted, particularly in view of the reported lack of toxicity associated with the preliminary clinical use of the drug as a radiosensitizer in man.