Validation plots in antenatal screening for Down's syndrome.

OBJECTIVE: To validate empirically the accuracy of antenatal Down's syndrome screening using the Integrated test, to compare this with other screening tests (including the Integrated test with the addition of cross trimester [CT] marker ratios) and to suggest how such validation analyses should be presented and interpreted. METHODS: Using data from 7809 unaffected and 27 Down's syndrome pregnancies that had had an Integrated test, risk estimates for various screening tests (maternal age, Double, Triple, Quadruple, Combined, Integrated and serum Integrated tests) that use Integrated test markers were categorized according to quintile categories of risk estimates of the 27 affected pregnancies. For each screening test, the median risk estimate for each category was plotted against the observed prevalence within each category. Such validation plots were also produced for the Integrated test with CT marker ratios by measuring the level of the serum markers in the trimester of pregnancy not already measured in stored samples of all affected and a one-in-five sample of unaffected pregnancies. The robustness of the method was assessed by repeating the analysis for the Integrated test after re-classifying affected pregnancies with low risk estimates as unaffected, simulating the underascertainment of cases. RESULTS: The validation plots (i) confirmed the accuracy of risk estimation for the different tests (by how close the points lay to the line of identity between predicted risk and observed prevalence), (ii) demonstrated the differences in screening performance of the different tests (by the range of risk spanned by the points and, in particular, the separation between the points representing the lowest risk and the next point), and (iii) are robust to underascertainment of affected pregnancies (by having little influence on the closeness of the points to the line of identity). CONCLUSION: The validation plot is a useful, simple and robust way to assess the validity of new screening methods, to assess the accuracy of risk estimation and to audit the performance of screening programmes.

Pediatric cardiac catheterization with same-day discharge.

A system was developed for cardiac catheterization in children without overnight hospital stay (called same-day discharge). Over a 4 year period, 233 children (aged 5 weeks to 20 years) had catheterization with same-day discharge staying an average of 11.8 hours in the hospital. In all but 1, no problems occurred after hospital discharge; 1 child required readmission for psoas tendinitis after retrograde aortography. Same-day discharge was safely applied regardless of the patient's age, diagnosis, and use of systemic heparinization, large-bore sheaths, retrograde arterial catheterization, or cineangiography. The hospital-related cost of pediatric cardiac catheterization was reduced 29% compared with that of the standard 42 hour hospital stay. Same-day discharge provides attractive elements to the physician and institution involved in cardiac catheterizations, for example: (1) improved medical care by a decrease in the length of hospitalization, (2) a significant reduction in medical costs, and (3) elimination of time pressure in training and teaching as well as therapeutic decision-making. Critical factors for the successful application of same-day discharge are coordination of multiple health care professionals and physician judgment of the patient's clinical status. We speculate that reassessment of other hospital-oriented procedures may foster the development of methods for improving medical care or reducing cost, or both.

Social status controls LH secretion and ovulation in female marmoset monkeys (Callithrix jacchus).

The suppression of ovulation in subordinate female marmosets was associated with suppressed pituitary LH secretion and reduced pituitary LH response to gonadotrophin-releasing hormone (GnRH). In subordinate females, basal plasma LH concentrations were commonly below 2 IU/l (n = 5) (maximum 10.7 IU/l). Plasma oestrogen concentrations were similarly low (maximum 0.62 nmol/l) and plasma progesterone concentrations of below 30 nmol/l confirmed the anovulatory condition. This infertility condition was rapidly reversed when subordinate females (n = 5) were removed from their social groups and housed singly, when plasma LH (maximum 140.0 IU/l) and oestrogen (maximum 7.84 nmol/l) concentrations increased preceding ovulation. Infertility was rapidly reimposed when these singly housed females were re-introduced to subordinate status in new social groups, when plasma LH concentrations fell to their previous low values within 4 days; no ovulation occurred thereafter. Plasma oestrogen levels also fell, but less dramatically. The luteal phases of three of the subordinate females were shortened following the re-instatement of subordinate status. The maximum LH response of subordinate females to the highest dose of GnRH (200 ng) was only 19.1 +/- 6.7 IU/l (mean +/- S.E.M.; n = 8): this contrasted with that in dominant females in either the follicular phase (40.0 +/- 13.3 IU/l; n = 6) or the luteal phase (126.7 +/- 24.9 IU/l; n = 10) of the ovarian cycle. These results suggest that the social suppression of fertility in subordinate female marmosets is mediated by impaired hypothalamic GnRH secretion. Such an immediate and precise behavioural control of LH secretion and ovulation is without equal in anthropoid primates.

Assay precision of serum alpha fetoprotein in antenatal screening for neural tube defects and Down's syndrome.

OBJECTIVES: To assess the impact of current serum alpha fetoprotein (AFP) assays on the performance of screening for open neural tube defects and Down's syndrome. METHODS: Maternal serum samples, collected between weeks 15 and 22 from 470 singleton pregnancies without neural tube defects or Down's syndrome, were assayed for AFP using an automated fluorometric immunoassay. The samples had been assayed for AFP using an in house radioimmunoassay with a lower precision ten years before. The variance of AFP using the radioimmunoassay was compared with that using the current fluorometric assay and then used to estimate the detection rates and false positive rates for neural tube defect and Down's syndrome screening. RESULTS: Current serum AFP assays are more precise. Using a cut off level of 2.5 multiples of the median, the false positive rate in screening for anencephaly and open spina bifida was 0.8% with the new assay compared with 2% using the previous assay. When screening for Down's syndrome, the false positive rate is reduced by about one percentage point without loss of detection. CONCLUSION: Improvements in the precision of maternal serum AFP measurement have led to small but useful improvements in screening for open neural tube defects and Down's syndrome. Published estimates of screening performance using such modern assays can be revised accordingly.

Circadian pattern of plasma melatonin concentrations in the marmoset monkey (Callithrix jacchus).

This study describes the concentrations of melatonin in plasma samples taken from marmoset monkeys (Callithrix jacchus) every 4 h over three 24-h periods. A circadian pattern of secretion was apparent, with higher levels recorded at night (20.00-08.00 h) than during the day (08.00-20.00 h) and a peak concentration at 20.00 h. There was a significant difference in the mean day and night concentrations (32.5 ± 4.5 pg/ml versus 49.0 ± 6.9 pg/ml, respectively) with individual concentrations ranging between<10-60 pg/ml in the day and 15-200 pg/ml at night. Circadian plasma melatonin concentrations were similar over the three 24-h periods, in male (n = 3) and female (n = 3) monkeys, and in dominant (cyclic, n = 5) and subordinate (acyclic, n = 4) females. The results show a less pronounced circadian profile in the marmoset than is seen in the human but a similar profile to that in the seasonally breeding rhesus monkey.

Stress factors influencing plasma cortisol levels and adrenal weights in Chinese water deer (Hydropotes inermis).

Stress responses were compared in Chinese water deer (Hydropotes inermis) exposed to different handling, management and disease factors by measuring plasma cortisol and adrenal gland weight. Healthy free-ranging deer shot as part of a management programme served as baseline controls; they had lower cortisol levels than either diseased deer or free-ranging deer that were either netted and manually restrained or anaesthetised by dart. Although darting appeared subjectively to be much less stressful to the deer than manual restraint, there was no significant difference in cortisol levels between the two groups. Hand-reared deer that were manually restrained in a similar manner to the free-ranging deer did not react behaviourally any less violently but showed significantly lower plasma cortisol levels. Adrenal glands of deer with various, mostly chronic, disease conditions weighed significantly more than those of healthy deer.

Insulin-like growth factors and cancer: no role in screening. Evidence from the BUPA study and meta-analysis of prospective epidemiological studies.

Insulin-like growth factor-1 (IGF-1), insulin-like growth factor-2 (IGF-2), and insulin-like growth factor binding protein-3 (IGFBP-3) were measured in frozen serum samples from 1051 men with cancer and 3142 controls in a nested case-control study from the British United Provident Association (BUPA) study cohort and associations with 14 cancers were examined, including prostate, colorectal, and lung. A meta-analysis of studies on these three cancer sites was also conducted. In the meta-analysis the odds ratio between the highest quartile IGF-1 group and the lowest quartile group was 1.31 (95% confidence interval (CI): 1.03-1.67) for prostate, 1.37 (1.05-1.78) for colorectal and 1.02 (0.80-1.31) for lung cancer, and for IGF-2 it was 0.72 (0.36-1.44) for prostate and 1.95 (1.26-3.00) for colorectal cancer. Results from the BUPA study were consistent with the estimates from the other studies. There were no statistically significant associations with IGFBP-3 and any of the cancer sites considered. Our results suggest that IGF-1, IGF-2, and IGFBP-3 measurements have no value in cancer screening, although IGF-1 and IGF-2 may be of aetiological significance in relation to colorectal and prostate cancer.

Extension of reproductive suppression by pheromonal cues in subordinate female marmoset monkeys, Callithrix jacchus.

Pheromonal signals from the dominant female marmoset monkey were implicated in maintaining the suppression of LH secretion and ovulation in socially subordinate females. When subordinate, and reproductively suppressed, female marmoset monkeys were removed from their group without scent contact with their dominant females, subordinate females in control group 1 (N = 8) and control group 2 (N = 5), ovulated 10.8 +/- 1.4 days and 10.4 +/- 0.8 days respectively (mean +/- s.e.m.) after separation. Subordinate females (N = 8) removed from their dominant female and group, but maintained in scent contact only with their dominant females, showed a delay in the onset of ovulation (31.0 +/- 6.4 days) compared with control groups 1 and 2. Plasma LH concentrations of subordinate females during the scent transfer phase were lower than in controls without scent transfer and comparable to those seen whilst the females were subordinates in groups. Contact of subordinate females with olfactory stimuli from dominant females therefore maintains the suppression of both LH secretion and ovulation in socially subordinate female marmosets. Such pheromonal cues provide evidence of a quantifiable link between dominant female marmosets and the maintenance of physiological suppression of reproduction in their female subordinates.

Sensory cues and the suppression of reproduction in subordinate female marmoset monkeys, Callithrix jacchus.

Subordinate female marmoset monkeys remain anovulatory and have low plasma concentrations of luteinizing hormone (LH) when maintained with their dominant females. Olfactory cues from the dominant female have been implicated in maintaining this reproductive suppression. Subordinate females that received either ablation of the vomeronasal organ (an accessory olfactory organ; n = 3), ablation of the main olfactory epithelium (n = 4), or both lesions (n = 5) did not ovulate in the following 7 weeks while housed with their dominant female. Plasma LH concentrations following either or both lesions were similar to pre-lesion concentrations. Olfactory lesions (verified by histological and behavioural trials) did not impair reproductive activity, as olfactory-lesioned dominant females underwent ovarian cycles of similar duration to intact dominant females. Lesioned subordinate females (n = 6), maintained in visual-only contact with their dominant female and group ovulated 29.1 +/- 9.3 days (mean +/- SEM) after physical separation from their dominant females; this first onset of ovulation was significantly delayed (P < 0.05) compared with intact subordinate females completely isolated from their dominant females and group (10.8 +/- 1.3 days, n = 8). Behavioural and visual cues together with olfaction all appear to play important roles in maintaining the suppression of ovulation in subordinate female marmoset monkeys.

Treatment of microfilaraemia in asymptomatic brugian filariasis: the efficacy and safety of the combination of single doses of ivermectin and diethylcarbamazine.

Although combinations of ivermectin and diethylcarbamazine (DEC) have been shown to be superior to either drug alone in the suppression of bancroftian microfilariae, their efficacy against infections with Brugia malayi has never been investigated. The present, open trial is the first on the efficacy and safety of a combination of single doses of ivermectin and DEC when used against microfilaraemias of brugian filariasis. Twenty-one, asymptomatic but microfilaraemic (109-6934 microfilariae/ml blood, with a median of 841/ml) men, aged 18-48 years, each received oral doses of ivermectin (400 micrograms/kg) and DEC (6 mg/kg) as a single treatment. Twelve hours post-treatment, 96.5%-100% of the microfilariae in each subject had been cleared and 12 of the subjects were amicrofilaraemic. A further reduction in microfilarial counts was evident 1 month post-treatment (mean clearance = 99.0%) and the counts continued to fall at least until the last follow-up, at 1 year post-treatment, when the mean clearance was 99.9% and 13 (68.4%) of the 19 subjects then investigated were amicrofilaraemic. All subjects experienced adverse reactions of one form or another, lasting for up to 48 h post-treatment; these included fever, myalgia, headache, and lethargy. Postural hypotension was recorded in two subjects and dilated, inflamed lymphatic channels were seen in another two. The combination of ivermectin and DEC demonstrated a microfilaricidal effect superior to that of either drug used alone, both in the initial rapid clearance of microfilariae and in sustaining the effect for 1 year. This finding has important implications for the control of lymphatic filariasis.

Urinary endocrine monitoring of the ovarian cycle and pregnancy in Goeldi's monkey (Callimico goeldii).

A non-invasive study of urinary hormones in 6 captive female Goeldi's monkeys provided accurate information on reproductive function. Conjugated oestrone accounted for 80-85% of the urinary oestrone and oestradiol measured. Radioimmunoassay measurements of conjugated oestrone provided a reliable indicator of cyclic ovarian function (mean cycle length: 24.1 +/- 0.9 days; n = 9) and pregnancy (gestation: 145, 155 days; n = 2). Measurements of urinary progesterone and pregnanediol glucuronide were only reliable as indicators of ovarian cyclicity. Elevations in urinary conjugated oestrone coincided with luteal-phase elevations of urinary progesterone and pregnanediol glucuronide. Urinary LH concentrations provided no indication of pituitary activity. However, the frequencies of female sexual solicitations of males were maximal when oestrone conjugate concentrations rose, suggesting a peri-ovulatory period. Ovulation was suppressed in 1 of 3 subordinate females housed in male-female-female trios.