The glucocorticoid receptor gene polymorphism N363S predisposes to more severe toxic side effects during pediatric acute lymphoblastic leukemia (ALL) therapy.

The survival rates in childhood acute lymphoid leukemia (ALL) have improved dramatically; however, patients still suffer from a variety of drug-related toxicities. Individualized therapy regimens promise the least toxic therapy regimen with the best hematologic outcome. Our aim was to investigate whether increased individual glucocorticoid sensitivity due to the N363S polymorphism of the glucocorticoid receptor increased susceptibility to steroid-related toxicities during ALL therapy. A total of 346 pediatric ALL patients were involved in the present study. N363S carrier status was investigated by allele-specific PCR. Clinical and laboratory signs of glucocorticoid-related toxicities, Day 8 prednisone response, and 5-year event-free survival were analyzed and compared retrospectively. Thirty-two of the 346 patients were heterozygous carriers (9.2 %). Hepatotoxicity (31.3 vs. 11.2 %, p = 0.004, carriers and non-carriers, respectively) and glucose metabolism abnormalities (18.8 vs. 3.8 %, p = 0.001, carriers and non-carriers, respectively) were significantly more frequent among carriers. There was no difference in the incidence of hypertension and encephalopathy/psychosis among carriers and non-carriers. Carriers were also more prone to have a combination of toxicities. All 363S carriers were good prednisone responders (100 %) and had significantly better 5-year event-free survival rates (93.1 vs. 71.86 %, p = 0.012), whereas among non-carriers there were more poor prednisone responders (8.28 %) and worse 5-year event-free survival rates. Patients with the N363S polymorphism in the glucocorticoid receptor are more prone to steroid-related toxicity during ALL therapy and should be monitored more closely. Patients with N363S polymorphism of the glucocorticoid receptor may be appropriate candidates for inclusion in the design of individualized therapies.

Functioning of families with primary school-age children conceived using anonymous donor sperm.

STUDY QUESTION: How do families with children conceived using donor sperm operate as the children grow up? SUMMARY ANSWER: Families with children aged 5-13 years conceived through anonymous donor sperm function well, when compared with other family types with children of the same developmental stage. WHAT IS KNOWN ALREADY: Previous studies on family relationships after donor sperm conception have been reassuring. However, these studies have suffered from methodological limitations due to small sample sizes, respondent biases and absence of appropriate controls. STUDY DESIGN, SIZE, DURATION: This study was an observational study comparing 79 'donor insemination' (DI) families with 987 'couple' families, 364 'single mother' and 112 'step-father' families as part of the Australian Institute of Family Studies Children and Family Life (CFL) study. CFL involved the collection of data on family functioning and child wellbeing from all resident parents through a Family and Child Questionnaire for the 'primary' parent (FACQ-P1) and a Family Relationship Questionnaire (FRQ-P2) for the 'other' parent. PARTICIPANTS/MATERIALS, SETTING, METHODS: All questionnaires were coded with the identity known only to the researchers. The outcomes studied included parent psychological adjustment, family functioning, couple relationship, parenting and parent-child relationship. Family types were compared, separately for mothers' and fathers' reports. The results presented are the estimated means for each family type based on the final model for each outcome: post hoc comparisons between family types are reported with 95% confidence limits. MAIN RESULTS AND THE ROLE OF CHANCE: With all of the outcomes considered, there was not one result where the DI families showed poorer functioning on average than the comparison groups. LIMITATIONS, REASON FOR CAUTION: The final sample size of DI families is 79 with an excellent response rate of nearly 80%. However, there remains some scope for response bias. WIDER IMPLICATIONS OF THE FINDINGS: This study further reassures us that families conceived with anonymous donor sperm do not function any differently from other family types.

Noninvasive measurement of physiological signals on a modified home bathroom scale.

A commercial bathroom scale with both handlebar and footpad electrodes was modified to enable measurement of four physiological signals: the ballistocardiogram (BCG), electrocardiogram (ECG), lower body impedance plethysmogram (IPG), and lower body electromyogram (EMG). The BCG, which describes the reaction of the body to cardiac ejection of blood, was measured using the strain gauges in the scale. The ECG was detected using handlebar electrodes with a two-electrode amplifier. For the lower body IPG, the two electrodes under the subject's toes were driven with an ac current stimulus, and the resulting differential voltage across the heels was measured and demodulated synchronously with the source. The voltage signal from the same two footpad electrodes under the heels was passed through a passive low-pass filter network into another amplifier, and the output was the lower body EMG signal. The signals were measured from nine healthy subjects, and the average signal-to-noise ratio (SNR) while the subjects were standing still was estimated for the four signals as follows: BCG, 7.6 dB; ECG, 15.8 dB; IPG, 10.7 dB. During periods of motion, the decrease in SNR for the BCG signal was found to be correlated to the increase in rms power for the lower body EMG (r = 0.89, p <; 0.01). The EMG could, thus, be used to flag noise-corrupted segments of the BCG, increasing the measurement robustness. This setup could be used for monitoring the cardiovascular health of patients at home.

Decreased hormone content of immune cells in children during acute lymphocytic leukemia (ALL) - effect of treatment.

Histamine, serotonin and triiodothyronine (T3) content of different circulating lymphocyte subsets of leukemic (acute lymphocytic leukemia, ALL) and non-leukemic (control) children were investigated by multicolor flow cytometry. The hormone contents of the cells were followed from the time of diagnosis till the end of treatment. Each hormone could be detected in every time in the investigated cell types, although the amounts of them changed during the treatment.T lymphocytes: Significantly lower amount of serotonin was found in each T cell subsets (Th, Tc and activated T lymphocytes) of leukemic children compared to the healthy control group at the time of diagnosis and it was permanently low during the maintenance therapy. The decreased amount of serotonin could be demonstrated in Tc and Th cells even at one year after the end of treatment. However, there was no alteration in the histamine and T3 content of T cell subsets in the time of diagnosis, but significant decrease was detected during the maintenance therapy and after treatment.NK cells: The serotonin and T3 contents of NK cells (both NK and NKT subsets) were significantly lower at the time of diagnosis and during the maintenance therapy. Similar decrease was detected in the case of serotonin in B cells. Although there was no difference in the T3 content of B cells at the time of diagnosis, significantly lower amounts could be detected during the therapy compared to the healthy control group. The serotonin concentration remained low for years after the end of treatment, both in B and NK cells. These observations might have diagnostic and prognostic importance.

A low-noise ac-bridge amplifier for ballistocardiogram measurement on an electronic weighing scale.

Ballistocardiography is a non-invasive technique for evaluating cardiovascular health. This note presents an ac-bridge amplifier for low-noise ballistocardiogram (BCG) recording from a modified weighing scale. The strain gauges in a commercial scale were excited by an ac source-square or sine wave-and the differential output voltage resulting from the BCG was amplified and demodulated synchronously with the excitation waveform. A standard BCG amplifier, with a simple dc-bridge excitation, was also built and the performance was compared to both the square- and sine-wave excited ac-bridge amplifiers. The total input-referred voltage noise (rms) integrated over the relevant BCG bandwidth of 0.3-10 Hz was found to be 30 nV (square wave source) or 25 nV (sine-wave source) for the ac-bridge amplifier and 52 nV for the standard amplifier: an improvement of 4.8 dB or 6 dB, respectively. These correspond to input-referred force noise (rms) values of 5 mN, 4 mN and 8.3 mN. The improvement in SNR was also observed in recorded waveforms from a seated subject whose BCG signal was measured with both dc- and ac-bridge circuits.

An 11 µ w, two-electrode transimpedance biosignal amplifier with active current feedback stabilization.

A novel two-electrode biosignal amplifier circuit is demonstrated by using a composite transimpedance amplifier input stage with active current feedback. Micropower, low gain-bandwidth product operational amplifiers can be used, leading to the lowest reported overall power consumption in the literature for a design implemented with off-the-shelf commercial integrated circuits (11 µW). Active current feedback forces the common-mode input voltage to stay within the supply rails, reducing baseline drift and amplifier saturation problems that can be present in two-electrode systems. The bandwidth of the amplifier extends from 0.05-200 Hz and the midband voltage gain (assuming an electrode-to-skin resistance of 100 kΩ) is 48 dB. The measured output noise level is 1.2 mV pp, corresponding to a voltage signal-to-noise ratio approaching 50 dB for a typical electrocardiogram (ECG) level input of 1 mVpp. Recordings were taken from a subject by using the proposed two-electrode circuit and, simultaneously, a three-electrode standard ECG circuit. The residual of the normalized ensemble averages for both measurements was computed, and the power of this residual was 0.54% of the power of the standard ECG measurement output. While this paper primarily focuses on ECG applications, the circuit can also be used for amplifying other biosignals, such as the electroencephalogram.

Non-invasive cardiac output trending during exercise recovery on a bathroom-scale-based ballistocardiograph.

Cardiac ejection of blood into the aorta generates a reaction force on the body that can be measured externally via the ballistocardiogram (BCG). In this study, a commercial bathroom scale was modified to measure the BCGs of nine healthy subjects recovering from treadmill exercise. During the recovery, Doppler echocardiogram signals were obtained simultaneously from the left ventricular outflow tract of the heart. The percentage changes in root-mean-square (RMS) power of the BCG were strongly correlated with the percentage changes in cardiac output measured by Doppler echocardiography (R(2) = 0.85, n = 275 data points). The correlation coefficients for individually analyzed data ranged from 0.79 to 0.96. Using Bland-Altman methods for assessing agreement, the mean bias was found to be -0.5% (+/-24%) in estimating the percentage changes in cardiac output. In contrast to other non-invasive methods for trending cardiac output, the unobtrusive procedure presented here uses inexpensive equipment and could be performed without the aid of a medical professional.

Robust ballistocardiogram acquisition for home monitoring.

The ballistocardiogram (BCG) measures the reaction of the body to cardiac ejection forces, and is an effective, non-invasive means of evaluating cardiovascular function. A simple, robust method is presented for acquiring high-quality, repeatable BCG signals from a modified, commercially available scale. The measured BCG waveforms for all subjects qualitatively matched values in the existing literature and physiologic expectations in terms of timing and IJ amplitude. Additionally, the BCG IJ amplitude was shown to be correlated with diastolic filling time for a subject with premature atrial contractions, demonstrating the sensitivity of the apparatus to beat-by-beat hemodynamic changes. The signal-to-noise ratio (SNR) of the BCG was estimated using two methods, and the average SNR over all subjects was greater than 12 for both estimates. The BCG measurement was shown to be repeatable over 50 recordings taken from the same subject over a three week period. This approach could allow patients at home to monitor trends in cardiovascular health.

Synergistic interaction of ABCB1 and ABCG2 polymorphisms predicts the prevalence of toxic encephalopathy during anticancer chemotherapy.

Polymorphisms of the ABCB1 (MDR1) and ABCG2 (BCRP) genes were reported to alter the expression and function of these drug transporters. Both proteins are present at the main pharmacokinetic barriers including the blood-brain barrier. Data from 291 children with acute lymphoblastic leukaemia were analysed in this retrospective study. ABCB1 3435T>C, 2677G>T/A, 1236C>T and ABCG2 421C>A, 34G>A genotypes were determined. Encephalopathy episodes were more frequent among those with ABCB1 3435TT genotype than in the 3435CC/CT group (odds ratio (OR) 3.5; P=0.03). Patients with the ABCG2 421A allele tended to have more complications than wild type homozygotes (OR=2.0; P=0.25). The rate of the adverse effect was similar in those harbouring no or only one of the predisposing genotypes, that is, either ABCB1 3435TT or ABCG2 421AA/AC. However, significantly more children suffered encephalopathy in the group with both predisposing genotypes (OR=12.3; P=0.005). In conclusion, these variations exert synergistic effect in predisposing patients to toxic neurological complications of chemotherapy.

Adolescence and other risk factors for Chlamydia trachomatis genitourinary infection in women in Melbourne, Australia.

OBJECTIVE: To establish the prevalence of and risk factors for Chlamydia trachomatis infection to determine the role of universal versus targeted testing. METHODS: A prospective study of 1107 women attending two sexual and reproductive health clinics in Melbourne, Australia, was carried out. A questionnaire was used to establish risk factors. Urine samples were tested for C. trachomatis by PCR. The main outcome measures were prevalence of and risk factors for C. trachomatis infection. RESULTS: Of 1107 recruitable women, 851 (76.9%) consented and were successfully tested. C. trachomatis was detected in 18 (4.8% (95% CI 2.9 to 7.5)) of 373 women in the inner city and eight (1.7% (95% CI (0.7 to 3.3)) of 478 women in the suburban clinic. Of women under 25 years, 17 (6.2% (95% CI 3.7 to 9.8)) of 273 in the inner city in contrast with three (1.7% (95% CI 0.4 to 5.0)) of 174 in the suburban clinic were infected. In the inner city clinic, age under 25 years (OR 5.4 (95% CI 0.7 to 41.5)), vaginal discharge (OR 4.1 (95% CI 1.5 to 11.1)), and recent change of sexual partner (OR 4.6 (95% CI 1.6 to 12.9)) were associated with C. trachomatis. In contrast, in the suburban clinic, only vaginal discharge (OR 3.5 (95% CI 0.9 to 14.3)) and recent change of sexual partner (OR 3.4 (95% CI 0.8 to 15.7)) were identified as risk factors. Multivariate analysis showed that recent change of partner (OR 4.5 (95% CI 1.5 to 13.8)) was the most strongly associated independent risk factor for infection in the inner city clinic. CONCLUSION: The high prevalence of C. trachomatis indicates that universal testing should be undertaken in the inner city clinic. Young age may not be a risk factor for C. trachomatis in more affluent populations with lower prevalence rates. No risk factors were identified with sufficient sensitivity and specificity to be useful for targeted testing. Prevalence and identifiable risk factors for C. trachomatis are not transferable between populations, even in the same city.

Surgical or medical treatment of polycystic ovary syndrome: a cost-benefit analysis.

With the availability of laparoscopic ovarian cautery, there has been a resurgence in interest in the surgical treatment of clomiphene citrate-resistant polycystic ovary syndrome (PCOS). Comparison of ovulation and pregnancy rates has found no difference in success rates between ovarian cautery and gonadotropin ovulation induction for such women. We have therefore compared the cost of laparoscopic ovarian cautery with that of a typical cycle of gonadotropin ovulation induction, and also found that there is little difference. Because of the potential advantages of ovarian cautery, we recommend this surgery as the next line of treatment if clomiphene citrate fails to induce ovulation in PCOS patients, before gonadotropins are introduced.

Serving rural Australia with reproductive health expertise.

This study aimed to review the use of reproductive health services in Family Planning clinics by women from rural (non-metropolitan) Australia through a retrospective analysis of data collected at clinics of seven state/territory Family Planning Organisations (FPO). From a total of 146 157 client visits to FPO clinics between July 1998 and June 1999, 42 497 (29.1%) were by clients who lived outside metropolitan areas. Some 97% of clients were women. Our results show the use of reproductive health services by women from rural areas was different from the services used by women from metropolitan areas. There were fewer male clients, more women over 40 years of age, and fewer clients from a non-English speaking background. More of the attendees had pension cards and fewer were privately insured. We concluded there is considerable demand for reproductive health services among the rural population and reproductive health care needs to be expanded to reach rural women.

Portable cell-based biosensor system using integrated CMOS cell-cartridges.

The use of cell-based biosensors outside of the laboratory has been limited due to many issues including preparation of the sample, maintenance of the biological environment, and integration of the electronics for data collection and analysis. This paper describes a system that addresses several of these issues with the development of an integrated silicon-polydimethylsiloxane cell-cartridge. The cell-cartridge contains a CMOS silicon chip that incorporates a digital interface, temperature control system, microelectrode electrophysiology sensors, and analog signal buffering. Additionally, the cell-cartridge supports two separate cell populations in two 10 microl sealed chambers that have independent fluidic channels for sample injection. A portable, microcontroller-based electronics system capable of monitoring the action potential (AP) activity within the cell-cartridges was also developed. The AP activities of cardiomyocyte syncytia in the two chambers differentially responded to the flow of a control medium versus the flow of a biochemical agent. The cell-cartridges and portable electronics system were used to successfully record AP activity from cardiomyocytes outside of the laboratory under realistic application conditions.

General purpose, field-portable cell-based biosensor platform.

There are several groups of researchers developing cell-based biosensors for chemical and biological warfare agents based on electrophysiologic monitoring of cells. In order to transition such sensors from the laboratory to the field, a general-purpose hardware and software platform is required. This paper describes the design, implementation, and field-testing of such a system, consisting of cell-transport and data acquisition instruments. The cell-transport module is a self-contained, battery-powered instrument that allows various types of cell-based modules to be maintained at a preset temperature and ambient CO(2) level while in transit or in the field. The data acquisition module provides 32 channels of action potential amplification, filtering, and real-time data streaming to a laptop computer. At present, detailed analysis of the data acquired is carried out off-line, but sufficient computing power is available in the data acquisition module to enable the most useful algorithms to eventually be run real-time in the field. Both modules have sufficient internal power to permit realistic field-testing, such as the example presented in this paper.

A genetically engineered cell-based biosensor for functional classification of agents.

Cell-based biosensors (CBBs) utilize whole cells to detect biologically active agents. Although CBBs have shown success in detecting the presence of biological agents, efforts to classify the type of agent based on functional activity have proven difficult because multiple biochemical pathways can lead to the same cellular response. However, a new approach using a genetically-engineered cell-based biosensor (GECBB) described in this paper translates this cross-talk noise into common-mode noise that can be rejected. The GECBB operates by assaying for an agent's ability to differentially activate two populations of cells, wild-type (WT) cells and cells genetically engineered to lack a specific receptor, knockout (KO) cells. Any biological agent that targets the knocked out receptor will evoke a response in the WT but not in the KO. Thus, the GECBB is exquisitely sensitive to agents that effect the engineered pathway. This approach provides the benefits of an assay for specific functional activity while simplifying signal analysis. The GECBB implemented was designed to be sensitive to agents that activate the beta 1-adrenergic receptor (beta 1-AR). This was achieved by using mouse cardiomyocytes in which the beta 1-AR had been knocked out. The cellular signal used in the GECBB was the spontaneous beat rate of the two cardiomyocyte syncitia as measured with microelectrode arrays. The GECBB was able to detect the beta-AR agonist isoproterenol (ISO) at a concentration of 10 microM (P<0.005).

The use of emergency contraception in Australasian emergency departments.

OBJECTIVE: To review the prescribing of emergency contraception by emergency departments in Australasia and compare it with other providers. METHODS: A postal questionnaire was sent to the director of each of the 79 Australasian College for Emergency Medicine accredited emergency departments in Australasia inquiring about the availability and prescribing habits for emergency contraception within each department. RESULTS: Of the 79 emergency departments, 69 (87.3%) responded to the questionnaire and were aware of the 'emergency contraception regimen'. The majority of departments prescribed appropriately (56%) and only one department did not arrange adequate follow up. Anti-emetics are always used by 45 departments (78.9%). Discussion of future contraceptive needs at the time of presentation was only undertaken by 25 departments (43.9%). Written clinical guidelines for emergency contraception were present in 28 departments (40.6%). CONCLUSIONS: Emergency departments are accessed by patients requesting contraception following unprotected intercourse or contraceptive failure. The prescribing of emergency contraception in Australasian emergency departments is comparable with other providers but substantial improvements could be made. Suggestions to assist this improvement include written clinical guidelines and patient information and purpose-made medication packs.

What is the probability of conception for couples entering an IVF program?

The outcome of 4225 couples undergoing 8207 in vitro fertilisation (IVF) cycles over a six year period has been analysed using life table analysis. Pregnancy was expressed as a 'clinical pregnancy - fetus visible on ultrasound' per stimulated cycle oocyte collection, with pregnancies obtained from frozen embryos being referred to the cycle where they were collected. We found that only 1 in 200 patients proceeded beyond six cycles and the cumulative per cent pregnant was 20.7% after the first cycle, with nearly half pregnant within three and over two-thirds being pregnant within six cycles. We find this is a useful way to present the chance of pregnancy to prospective couples.

Lysing bacterial spores by sonication through a flexible interface in a microfluidic system.

Cell disruptions using ultrasonic energy transmitted through a flexible interface into a liquid region has limitations because the motion of the vibrating tip is not completely transferred into the liquid. To ensure that some degree of contact will be maintained between the ultrasonic horn tip and the flexible interface, the liquid must be pressurized. The pressure conditions that yield consistent coupling between the ultrasonic horn tip and the liquid region were explored in this study by using an analytical model of the system and test fixture experiments. The nature of the interaction between the horn tip and the flexible interface creates pulses of positive pressure rises, increase in temperature, streaming flow, and almost no cavitation in the liquid. There was sufficient energy to create a cloud of microspheres, or beads, that maintain a consistent pattern of ballistic motion in the liquid. The sonication was found to be repeatable by studying video recordings of bead motion and was shown to be statistically consistent using measurements of temperature rise. Sonication of bacterial spores to obtain measurements of released nucleic acid and SEM images of damaged spores were used to verify the effects of liquid pressure on the horn-interface-liquid coupling.

A pre-coital pill? A preliminary in vitro study.

The use of the progestogen-only pill as a 'pre-coital contraceptive' was tested by in vitro studies of sperm-mucus interaction. The results suggest that a single tablet of levonorgestrel 30 microg, or norethisterone 350 microg, was effective in preventing sperm migration in the cervical mucus about 12 hours later. This suggests that the progestogen-only pill may be effective as a 'morning before pill'.

The use of family planning services by non-English speaking background (NESB) women.

This study was undertaken to determine the proportion of family planning organization clients who are from a non-English speaking background (NESB), to analyse the services they used, and to compare it to the services used by other clients. Analysis of clinic data sheets from the 8 State/Territory family planning organizations (FPO) was conducted. From a total of 185,879 client visits in FPO clinics between July, 1996 and June, 1997, 27,349 (14.7%) were from NESB. The proportion of clients with NESB was quite similar to that in the community. This means that in general, FPOs are reaching their share of clients with NESB. The patterns of reproductive health services used varied between NESB women compared to English speaking women.