Practical considerations for the measurement of free light chains in serum

Background: A new immunoassay for free light chain measurements has been reported to be useful for the diagnosis and monitoring of monoclonal light chain diseases and nonsecretory myeloma. We describe experience with and some potential pitfalls of the assay. Methods: The assay was assessed for precision, sample type and stability, recovery, and harmonization of results between two analyzers on which the reagents are used. Free-light-chain concentrations were measured in healthy individuals (to determine biological variation), patients with monoclonal gammopathy of undetermined significance, myeloma patients after autologous stem cell transplants, and patients with renal disease. Results: Analytical imprecision (CV) was 6-11% for kappa and A free-light-chain measurement and 16% for the calculated kappa/lambda ratio. Biological variation was generally insignificant compared with analytical variation. Despite the same reagent source, values were not completely harmonized between assay systems and may produce discordant free-light-chain ratios. In some patients with clinically stable myeloma, or post transplantation, or with monoclonal gammopathy of undetermined significance, free-light-chain concentration and ratio were within the population reference interval despite the presence of monoclonal intact immunoglobulin in serum. In other patients with monoclonal gammopathy of undetermined significance, values were abnormal although there was no clinical evidence of progression to multiple myeloma. Conclusions: The use of free-light-chain measurements alone cannot differentiate some groups of patients with monoclonal gammopathy from healthy individuals. As with the introduction of any new test, it is essential that more scientific data about use of this assay in different subject groups are available so that results can be interpreted with clinical certainty. (C) 2003 American Association for Clinical Chemistry.

The Scientific Basis for High-Intensity Interval Training: Optimising Training Programmes and Maximising Performance in Highly Trained Endurance Athletes

While the physiological adaptations that occur following endurance training in previously sedentary and recreationally active individuals are relatively well understood, the adaptations to training in already highly trained endurance athletes remain unclear. While significant improvements in endurance performance and corresponding physiological markers are evident following submaximal endurance training in sedentary and recreationally active groups, an additional increase in submaximal training (i.e. volume) in highly trained individuals does not appear to further enhance either endurance performance or associated physiological variables [e.g. peak oxygen uptake (V-dot O2peak), oxidative enzyme activity]. It seems that, for athletes who are already trained, improvements in endurance performance can be achieved only through high-intensity interval training (HIT). The limited research which has examined changes in muscle enzyme activity in highly trained athletes, following HIT, has revealed no change in oxidative or glycolytic enzyme activity, despite significant improvements in endurance performance (p < 0.05). Instead, an increase in skeletal muscle buffering capacity may be one mechanism responsible for an improvement in endurance performance. Changes in plasma volume, stroke volume, as well as muscle cation pumps, myoglobin, capillary density and fibre type characteristics have yet to be investigated in response to HIT with the highly trained athlete. Information relating to HIT programme optimisation in endurance athletes is also very sparse. Preliminary work using the velocity at which V-dot O2max is achieved (Vmax) as the interval intensity, and fractions (50 to 75%) of the time to exhaustion at Vmax (Tmax) as the interval duration has been successful in eliciting improvements in performance in long-distance runners. However, Vmax and Tmax have not been used with cyclists. Instead, HIT programme optimisation research in cyclists has revealed that repeated supramaximal sprinting may be equally effective as more traditional HIT programmes for eliciting improvements in endurance performance. Further examination of the biochemical and physiological adaptations which accompany different HIT programmes, as well as investigation into the optimal HIT programme for eliciting performance enhancements in highly trained athletes is required.

Callyspongynes A and B: New polyacetylenic lipids from a southern Australian marine sponge, Callyspongia sp.

A Callyspongia sp. collected by SCUBA off Barwon Heads, Australia, has afforded two new polyacetylenic lipids, callyspongynes A and B, the structures of which were assigned by spectroscopic analysis and chemical derivatization.

Interval breast cancers in an Australian mammographic screening program

Objective: To determine the incidence of interval cancers which occurred in the first 12 months after mammographic screening at a mammographic screening service. Design: Retrospective analysis of data obtained by crossmatching the screening Service and the New South Wales Central Cancer Registry databases. Setting: The Central & Eastern Sydney Service of BreastScreen NSW. Participants: Women aged 40-69 years at first screen, who attended for their first or second screen between 1 March 1988 and 31 December 1992. Main outcome measures: Interval-cancer rates per 10 000 screens and as a proportion of the underlying incidence of breast cancer (as estimated by the underlying rate in the total NSW population). Results: The 12-month interval-cancer incidence per 10 000 screens was 4.17 for the 40-49 years age group (95% confidence interval [CI], 1.35-9.73) and 4.64 for the 50-69 years age group (95% CI, 2.47-7.94). Proportional incidence rates were 30.1% for the 40-49 years age group (95% CI, 9.8-70.3) and 22% for the 50-69 years age group (95% CI, 11.7-37.7). There was no significant difference between the proportional incidence rate for the 50-69 years age group for the Central & Eastern Sydney Service and those of major successful overseas screening trials. Conclusion: Screening quality was acceptable and should result in a significant mortality reduction in the screened population. Given the small number of cancers involved, comparison of interval-cancer statistics of mammographic screening programs with trials requires age-specific or age-adjusted data, and consideration of confidence intervals of both program and trial data.

Retinal and lenticular ultrastructure in the aestivating salamanderfish, Lepidogalaxias salamandroides (Galaxiidae, Teleostei) with special reference to a new type of photoreceptor mosaic

The salamanderfish, Lepidogalaxias salamandroides (Galaxiidae, Teleostei) is endemic to southwestern Australia and inhabits shallow, freshwater pools which evaporate during the hot summer months. Burrowing into the substrate in response to falling water levels allows these fish to aestivate for extended periods of time while encapsulated in a mucous cocoon even when the pools contain no water. Only a few minutes after a major rainfall, these fish emerge into relatively clear water which subsequently becomes laden with tannin, turning the water black and reducing the pH to approximately 4.3. As part of a large study of the visual adaptations of this unique species, the retinal and lenticular morphology of the aestivating salamanderfish is examined at the level of the light and electron microscopes. The inner retina is highly vascularised by a complex system of vitreal blood vessels, while the outer retina receives a blood supply by diffusion from a choriocapillaris. This increased retinal blood supply may be an adaptation for reducing the oxygen tension during critical periods of aestivation. Large numbers of Muller cells traverse the thickness of the retina from the inner to the outer limiting membranes. The ganglion cells are arranged in two ill-defined layers, separated from a thick inner nuclear layer containing two layers of horizontal cells by a soma-free inner plexiform layer. The photoreceptors can be divided into three types typical of many early actinopterygian representatives; equal double cones, small single cones and large rods (2:1:1). These photoreceptors are arranged into a unique regular square mosaic comprising a large rod bordered by four equal double cones with a small single cone located at the corner of each repeating unit. The double cones may optimise perception of mobile prey which it tracks by flexion of its head and neck and the large rods may increase sensitivity in the dark tannin-rich waters in which it lives. Each single cone also possesses a dense collection of polysomes and glycogen (a paraboloid) beneath its ellipsoid, the first such finding in teleosts. The retinal pigment epithelium possesses melanosomes, pha,oocytes and a large number of mitochondria. The anatomy of the retina and the photoreceptor mosaic is discussed in relation to the primitive phylogeny of this species and its unique life history.

Assessment of transient gene expression in plant tissues using the green fluorescent protein as a reference

Four different promoters (35S and enhanced 35S of the cauliflower mosaic virus, polyubiquitin of maize and actin1 of rice) were compared in a transient assay using maize leaves and particle bombardment. A gene encoding the jellyfish green fluorescent protein (GFP) driven by the 358 promoter was used as an internal standard to monitor the effectiveness of each bombardment. Normalisation of the transient expression assay using the GFP reference significantly reduced the variability between separate bombardments and allowed for a rapid and accurate evaluation of different promoters in microprojectile-bombarded leaves.

Predicting composition of leg sections with anthropometry and bioelectrical impedance analysis using magnetic resonance imaging as reference

Magnetic resonance imaging (MRI) was used to evaluate and compare with anthropometry a fundamental bioelectrical impedance analysis (BIA) method for predicting muscle and adipose tissue composition in the lower limb. Healthy volunteers (eight men and eight women), aged 41 to 62 years, with mean (S.D.) body mass indices of 28.6 (5.4) kg/m(2) and 25.1 (5.4) kg/m(2) respectively, were subjected to MRI leg scans, from which 20-cm sections of thigh and IO-cm sections of lower leg (calf) were analysed for muscle and adipose tissue content, using specifically developed software. Muscle and adipose tissue were also predicted from anthropometric measurements of circumferences and skinfold thicknesses, and by use of fundamental BIA equations involving section impedance at 50 kHz and tissue-specific resistivities. Anthropometric assessments of circumferences, cross-sectional areas and volumes for total constituent tissues matched closely MRI estimates. Muscle volume was substantially overestimated (bias: thigh, -40%; calf, -18%) and adipose tissue underestimated (bias: thigh, 43%; calf, 8%) by anthropometry, in contrast to generally better predictions by the fundamental BIA approach for muscle (bias:thigh, -12%; calf, 5%) and adipose tissue (bias:thigh, 17%; calf, -28%). However, both methods demonstrated considerable individual variability (95% limits of agreement 20-77%). In general, there was similar reproducibility for anthropometric and fundamental BIA methods in the thigh (inter-observer residual coefficient of variation for muscle 3.5% versus 3.8%), but the latter was better in the calf (inter-observer residual coefficient of variation for muscle 8.2% versus 4.5%). This study suggests that the fundamental BIA method has advantages over anthropometry for measuring lower limb tissue composition in healthy individuals.

The ocular morphology of the southern hemisphere lamprey Geotria australis gray with special reference to optical specialisations and the characterisation and phylogeny of photoreceptor types

This paper describes the ocular morphology of young adults of the southern hemisphere lamprey Geotria australis, the sole representative of the Geotriidae, and makes comparisons with those of holarctic lampreys (Petromyzontidae). As previously reported for the holarctic lamprey Ichthyomyzon unicuspis [Collin and Fritzsch, 1993], the lens of G. australis is non-spherical and possesses a cone-shaped posterior that may be capable of mediating variable focus. The avascular retina of G. australis is well differentiated, containing three retinal ganglion cell populations, three layers of horizontal cells and three photoreceptor types, in contrast to petromyzontids that contain only two photoreceptor types (short and long), G. australis possesses one rod-like (R1) and two cone-like (C1 and C2) photoreceptors. Although the rodlike receptor in G. australis may be homologous with the short receptors of holarctic lampreys, the two cone-like receptors have morphological characteristics that differ markedly from those of the long receptors of their holarctic counterparts. The features which distinguish the two cone-like receptors from those of the long receptor type in holarctic lampreys are the characteristics of the mitochondria and the presence of large amounts of two different types of stored secretory material in the endoplasmic reticulum of the myoid (refractile bodies). The endoplasmic reticulum of each receptor type has a different shape and staining profile and is polymorphic, each showing a continuum of distension. It is proposed that the presence of two cone-like photoreceptors with different characteristics would increase the spectral range of G. australis and thus be of value during the parasitic phase, when this lamprey lives in the surface marine waters. The irideal flap, present in G. australis but not petromyzontids, would assist in reducing intraocular flare during life in surface waters. The results of this study, which are discussed in the context of the proposed evolution of lampreys, emphasise that it is important to take into account the characteristics of the eyes of southern hemisphere lampreys when making generalizations about the eyes of lampreys as a whole.

Impact of increasing the re-supply interval on the seasonality of subsidised prescription use in Australia

Objective: To evaluate the impact of increasing the minimum resupply period for prescriptions on the Pharmaceutical Benefits Scheme (PBS) in November 1994. The intervention was designed to reduce the stockpiling of medicines used for chronic medical conditions under the PBS safety net. Methods: Interrupted times series regression analyses were performed on 114 months of PBS drug utilisation data from January 1991 to June 2000. These analyses assessed whether there had been a significant interaction between the onset of the intervention in November 1994 and the extreme levels of drug utilisation in the months of December (peak utilisation) and January (lowest utilisation) respectively. Both serial and 12-month lag autocorrelations were controlled for. Results: The onset of the intervention was associated with a significant reduction in the December peak in drug utilisation; after the introduction of the policy there were 1,150,196 fewer proscriptions on average or that month (95% Cl 708,333-1,592,059). There was, however, no significant change in the low level of utilisation in January. The effect of the policy appears to be decreasing across successive postintervention years. though the odds of a prescription being dispensed in December remained significantly lower in 1999 compared to each of the pre-intervention years (11% vs. 14%) Conclusion: Analysis of the impact of increasing the re-supply period for PBS prescriptions showed that the magnitude of peak utilisation in December had been markedly reduced by the policy, though this effect appears to be decreasing over time. Continued monitoring and policy review is warranted in order to ensure that the initial effect of the intervention be maintained.

Acute high-intensity interval training improves T-vent and peak power output in highly trained males.

This study examined the effects of four high-intensity interval-training (HIT) sessions performed over 2 weeks on peak volume of oxygen uptake (VO2peak), the first and second ventilatory thresholds (UT VT2) and peak power output (PPO) in highly trained cyclists. Fourteen highly trained male cyclists (VO2peak = 67.5 +/- 3.7 ml . kg(-1) . min(-1)) performed a ramped cycle test to determine VO2peak VT1 VT2, and PPO. Subjects were divided equally into a HIT group and a control group. The HIT group performed four HIT sessions (20 x 60 s at PPO, 120 s recovery); the V-02peak test was repeated <I wk after the HIT program. Control subjects maintained their regular training program and were reassessed under the same timeline. There was no change in V0(2peak) for either group; however, the HIT group showed a significantly greater increase in VT1, (+22% vs. -3%), VT2 (+15% vs. -1%), and PPO (+4.3 vs. -.4%) compared to controls (all P <.05). This study has demonstrated that HIT can improve VT1, VT2,, and PPO, following only four HIT sessions in already highly trained cyclists.

Infrarenal aortic diameter predicts all-cause mortality

Objective - To assess the relationship between infrarenal aortic diameter and subsequent all-cause mortality in men aged 65 years or older. Methods and Results - Aortic diameter was measured using ultrasound in 12 203 men aged 65 to 83 years as part of a trial of screening for abdominal aortic aneurysms. A range of cardiovascular risk factors was also documented. Mortality over the next 3 to 7 years was assessed using record linkage. Initial aortic diameter was categorized into 10 intervals, and the relationship between increasing diameter and subsequent mortality was explored using Cox proportional hazard models. Median diameter increased from 21.4 mm in the youngest men to 22.1 mm in the oldest men. The cumulative all-cause mortality increased in a graded fashion with increasing aortic diameter. Using the diameter interval 19 to 22 mm as the reference, the adjusted hazard ratio for all-cause mortality increased from 1.26 (95% CI: 1.09, 1.44; P = 0.001) for aortic diameters of 23 to 26 mm to 2.38 (95% CI: 1.22, 4.61; P = 0.011) for aortic diameters of 47 to 50 mm. Analysis of causes of death indicated that cardiovascular disease was an important contributor to this increase. Conclusion - Infrarenal aortic diameter is an independent marker of subsequent all-cause mortality.

The relationship between prepulse inhibition and perceived intensity of the blink-eliciting stimulus: Stimulus intensity and lead interval effects

The hypothesis that prepulse inhibition of the blink reflex reflects a transient process that protects preattentive processing of the prepulse was investigated. Participants were presented with pairs of blink-eliciting noises, with some noises preceded by a prepulse, and were asked to rate the intensity of the second noise relative to the first. Inhibition of blink amplitude was greater for a 110 dB(A) noise than for a 95 dB(A) noise with a 120 ms lead interval, whereas there was no difference with a 30 ms lead interval. The reduction in perceived intensity was greater for the 110 dB(A) noise than for the 95 dB(A) noise with the 120 ms lead interval, but not with the 30 ms lead interval. The parallel results support an association between prepulse inhibition and perceived intensity. However, the prepulse did not reduce intensity ratings relative to control trials in some conditions, suggesting that prepulse inhibition is not always associated with an attenuation of the impact of the blink-eliciting stimulus.