Low tacrolimus concentrations and increased risk of early acute rejection in adult renal transplantation

Background. A retrospective analysis was performed on adult renal transplant recipients to evaluate the relationship between tacrolimus trough concentrations and the development of rejection in the first month after transplant. Methods. A total of 349 concentrations from 29 patients, measured by enzyme-linked immunosorbent assay (ELISA), were recorded. Based on an increased serum creatinine, 12 patients were considered to have organ rejection. Rejection was confirmed by biopsy in five of these. The median trough concentration of tacrolimus over the first month of therapy, or until the time of first rejection was compared in rejecters vs non-rejecters. Results. Median trough concentrations of tacrolimus were found to be lower in biopsy-proven rejecters vs non-rejecters (P=0.03) and all rejecters vs nonrejecters (P = 0.04). The average median concentration (+/- SD) in the biopsy-proven rejecter group was 5.09 +/-1.16 ng/ml, compared to 9.20 +/-3.52 ng/ml in the non-rejecter group. After exclusion of an outlier, the average median concentration in all rejecters was 5.57 +/-1.47 ng/rnl, compared with 9.20 +/-3.52 ng/ml in non-rejecters. A rejection rate of 55% was found for patients with a median trough concentration between 0 and 10 ng/ml. This compared with no observed rejection in patients with a median concentration between 10 and 15 ng/ml. Conclusion. A significant relationship exists between organ rejection and median tacrolimus trough concentrations in the first month post-transplant, with patients displaying low concentrations more likely to reject. In order to minimize rejection in the first month after renal transplantation, trough concentrations greater than 10 ng/ml must be achieved.

Seedling responses of three Australian tree species to toxic concentrations of zinc in solution culture

A frequently desired outcome when rehabilitating Zn toxic sites in Australia is to establish a self-sustaining native ecosystem. Hence, it is important to understand the tolerance of Australian native plants to high concentrations of Zn. Very little is known about the responses of Australian native plants, and trees in particular, to toxic concentrations of Zn. Acacia holosericea, Eucalyptus camaldulensis and Melaleuca leucadendra plants were grown in dilute solution culture for 10 weeks. The seedlings (42 days old) were exposed to six Zn treatments viz., 0.5, 5, 10, 25, 50 and 100 muM. The order of tolerance to toxic concentrations of Zn was E. camaldulensis > A. holosericea > M. leucadendra, the critical external concentrations being approximately 20, 12 and 1.5 muM, respectively. Tissue Zn concentrations increased as solution Zn increased for all species. Root tissue concentrations were higher than shoot tissue concentrations at all solution Zn concentrations. The critical tissue Zn concentrations were approximately 85 and 110 mug g(-1) DM for M. leucadendra, 115 and 155 mug g(-1) DM for A. holosericea and 415 and 370 mug g(-1) DM for E. camaldulensis for the youngest fully expanded leaf and total shoots, respectively. The results from this paper provide the first comprehensive combination of growth responses, critical external concentrations, critical tissue concentrations and plant toxicity symptoms for three important Australian genera, viz., Eucalyptus, Acacia and Melaleuca, for use in the rehabilitation of potentially Zn toxic sites.

Relationships between crude protein and mineral concentrations in alfalfa and value of alfalfa silage as a mineral source for periparturient cows

One hundred and eight samples from three cultivars of alfalfa were obtained from three cuttings in 1996-1998 to evaluate the relationship between crude protein (CP) and mineral concentrations of alfalfa with cutting and maturation. The CP content drastically decreased from 27.9 to 11.4% on DM with maturity. Highly positive correlations were observed between CP and K in the first and the second cutting of alfalfa. The Ca content remained almost constant throughout the growth period. Four multiparous Holstein cows were assigned an alfalfa silage diet or an orchardgrass silage diet from 3 weeks prepartum to 1 week postpartum to examine the effect on the mineral balance. In the prepartum and postpartum diet, the roughage to concentrate ratio was 70:30 and 50:50, with alfalfa being 50 and 100% of the roughage, respectively. The alfalfa contained 1.93% of K. No metabolic disorders occurred, but the body weight decreased drastically from 1 to 6 days postpartum with each diet because of the high milk production immediately after the parturition. Positive retention of N, Ca, P, Mg, and K was observed prepartum, whereas the cows had negative N and mineral retention from 2 to 4 days postpartum. The Ca and P absorption, and Mg retention of cows with the alfalfa diet were higher than with the grass diet. The plasma Ca and inorganic P were not affected by diet, but the plasma PTH at parturition and plasma hydroxyproline from 1 week prepartum to 1 week postpartum were higher with the alfalfa diet. These results suggest that the low K alfalfa is suitable not only to prevent the incidence of milk fever but also to increase Ca, P and Mg utilization of periparturient cows, but the mineral supplementation is needed for the postpartum cows immediately after the parturition. (C) 2001 Elsevier Science B.V. All rights reserved.

The gene encoding the immunoregulatory signaling molecule CMRF-35A localized to human chromosome 17 in close proximity to other members of the CMRF-35 family

The immunoregulatory signaling (IRS) family includes several molecules, which play major roles in the regulation of the immune response. The CMRF-35A and CMRF-35H molecules are two new members of the IRS family of molecules, that are found on a wide variety of haemopoietic lineages. The extracellular functional interactions of these molecules is presently unknown, although CMRF-35H on initiate an inhibitory signal and is internalized when cross-linked. In this paper, we described the gene structure for the CMRF-35A gene and its localization to human chromosome 17. The gene consists of four exons spanning approximately 4.5 kb. Exon 1 encodes the 5' untranslated region and leader sequence, exon 2 encodes the immunoglobulin (Ig)-like domain, exon 3 encodes the membrane proximal region and exon 4 encodes the transmembrane region, the cytoplasmic tail and the 3' untranslated region. A region in the 5' flanking sequence of the CMRF-35A gene, that promoted expression of a reporter gene was identified. The genes for the CMRF-35A and CMRF-35H molecules are closely linked on chromosome 17. Similarity between the Ig-like exons and the preceding intron of the two genes suggests exon duplication was involved in their evolution. We also identified a further member of the CMRF-35 family, the CMRF-35J pseudogene. This gene appears to have arisen by gene duplication of the CMRF-35A gene. These three loci-the CMRF-35A, CMRF-35J and CMRF-35H genes-form a new complex of IRS genes on chromosome 17.

Significance of serum early pregnancy factor concentrations during pregnancy and embryonic development in Sminthopsis macroura (Spencer) (Marsupialia : Dasyuridae)

Marsupial pregnancy differs from that in eutherians in duration, placentation and hormonal profile so much so that maternal recognition of pregnancy may not occur in polyovular marsupials. However, a comparison of gravid and non-gravid uteri reveals differences indicative of histological and physiological adaptations to pregnancy. In the present study, the hypothesis that embryo-maternal signalling occurs in polyovular marsupials was tested by examining serum from non-pregnant and pregnant Sminthopsis macroura for the presence of early pregnancy factor (EPF), a serum protein secreted by the ovary in response to the presence of a newly fertilized egg in the oviduct. EPF is detectable in the serum of pregnant, but not in non-pregnant, females in all eutherians studied to date. In the present study, EPF was detected in S. macroura serum by the rosette inhibition test during the first 9 days of the 10.7 day gestation period in this marsupial. However, EPF was not detected on day 10, just before parturition, or in non-pregnant or preovulatory animals. Immunohistochemical analysis of ovaries from gravid and non-gravid animals demonstrates that EPF is found in the capillaries, interstitial spaces and secretory cells of the corpus luteum. It is concluded that the spatiotemporal pattern of EPF activity described strongly indicates that maternal recognition of pregnancy in marsupials is mediated, at least in part, by EPF. Because the endocrinological milieu is the same in pregnant and non-pregnant marsupials, the possibility of using marsupials as an experimental system for studying EPF function unconfounded by hormonal effects is presented.

Reduced Red Cell 2,3-Diphosphoglycerate Concentrations in Critical Illness without Decreased In Vivo P50

We investigated whether red cell 2,3-diphosphoglycerate (2,3-DPG) concentrations are reduced in critical illness, whether acidaemia, hypophosphataemia or anaemia influence 2,3-DPG, and whether there is any net effect on in vivo P50. Twenty healthy, non-smoking, male volunteers were compared with 20 male intensive care patients with APACHE 2 scores > 20 on the preceding day. Those transfused in this time were excluded. Venous red cell 2,3-DPG concentrations were measured in both groups. In the patient group, routine multichannel biochemical profile and arterial blood gas analysis were also performed and in vivo P50 calculated. The mean 2,3-DPG concentration was significantly lower in the patient group than in the controls (4.2 +/-1.3 mmoll/l vs 4.9 +/-0.5 mmol/l, P=0.016). The patients were well oxygenated (lowest arterial PO2=75 mm Hg) and showed a tendency to acidaemia (median pH 7.37, range 7.06 to 7.48) and anaemia (median haemoglobin concentration 113 g/l, range 89 to 154 g/l). By linear regression of patient data, pH had a significant effect on 2,3-DPG concentrations (r=0.6, P=0.011). Haemoglobin and phosphate concentrations did not, but there were few abnormal phosphate values. There was no correlation between 2,3-DPG concentrations and in vivo P50 (r(2) less than or equal to 0.08). We conclude that 2,3-DPG concentrations were reduced in a broad group of critically ill patients. Although this would normally reduce the P50, the reduction was primarily linked with acidaemia, which increases the P50. Overall, there was no net effect on the P50 and thus no affinity-related decrease in tissue oxygenation.

Magnetic-field-induced superconductivity in layered organic molecular crystals with localized magnetic moments

l-(BETS)2FeCl4 undergoes transitions from an antiferromagnetic insulator to a metal and then to a superconductor as a magnetic field is increased. We use a Hubbard-Kondo model to clarify the role of the Fe31 magnetic ions in these phase transitions. In the high-field regime, the magnetic field acting on the electron spins is compensated by the exchange field He due to the magnetic ions. We show how He can be extracted from the observed splitting of the Shubnikov–de Haas frequencies. We predict the field range for field-induced superconductivity in other materials.

Dry matter production and boron concentrations of vegetative and reproductive tissues of canola and sunflower plants grown in nutrient solution

Canola (Brassica napus L.) and sunflower (Helianthus annuus L.), two important oilseed crops, are sensitive to low boron (B) supply. Symptoms of B deficiency are often more severe during the reproductive stage, but it is not known if this is due to a decreased external B supply with time or an increased sensitivity to low B during this stage. Canola and sunflower were grown for 75 days after transplanting (DAT) in two solution culture experiments using Amberlite (IRA-743) B-specific resin to maintain constant B concentration in solution over the range 0.6 - 53 muM. Initially, the vegetative growth of both crops was good in all treatments. With the onset of the reproductive stage, however, severe B deficiency symptoms developed and growth of canola and sunflower was reduced with less than or equal to 0.9 and less than or equal to 0.7 muM B, respectively. At these concentrations, reproductive parts failed to develop. The critical B concentration (i.e. 90% of maximum shoot dry matter yield) in the youngest opened leaf was 18 mg kg(-1) in canola and 25 mg kg(-1) in sunflower at 75 DAT. The results of this study indicate that the reproductive stage of these two oilseed crops is more sensitive than the vegetative stage to low B supply.

Acute stress hyperglycemia in cats is associated with struggling and increased concentrations of lactate and norepinephrine

We characterized the changes in blood glucose concentrations in healthy cats exposed to a short stressor and determined the associations between glucose concentrations, behavioral indicators of stress, and blood variables implicated in stress hyperglycemia (plasma glucose, lactate, insulin, glucagon, cortisol, epinephrine, and norepinephrine concentrations). Twenty healthy adult cats with normal glucose tolerance had a 5-minute spray bath. Struggling and vocalization were the most frequent behavioral responses. There was a strong relationship between struggling and concentrations of glucose and lactate. Glucose and lactate concentrations increased rapidly and significantly in all cats in response to bathing, with peak concentrations occurring at the end of the bath (glucose baseline 83 mg/dL, mean peak 162 mg/dL; lactate baseline 6.3 mg/dL, mean peak 64.0 mg/dL). Glucose response resolved within 90 minutes in 12 of the 20 cats. Changes in mean glucose concentrations were strongly correlated with changes in mean lactate (r =.84; P

Making decisions about treatment for localized prostate cancer

Objective To describe the decision-making processes used by men diagnosed with localized prostate cancer who were considering treatment. Patients and methods Men newly diagnosed with localized prostate cancer from outpatient urology clinics and urologist's private practices were approached before treatment. Their decision-making processes and information-seeking behaviour was assessed; demographic information was also obtained. Results Of 119 men approached, 108 (90%) were interviewed; 91% reported non-systematic decision processes, with deferral to the doctor, positive and negative recollections of others' cancer experiences, and the pre-existing belief that surgery is a better cancer treatment being most common. For systematic information processing the mean (SD, range) number of items considered was 4.19 (2.28, 0-11), with 57% of men considering four or fewer treatment/medical aspects of prostate cancer. Men most commonly considered cancer stage (59%), urinary incontinence (55%) and impotence (51%) after surgery, and low overall mortality (45%). Uncertainty about probabilities for cure was reported by 43% of men and fear of cancer spread by 37%. Men also described uncertainty about the probabilities of side-effects (27%), decisional uncertainty (25%) and anticipated decisional regret (18%). Overall, 73% of men sought information about prostate cancer from external sources, most commonly the Internet, followed by family and friends. Conclusions In general, men did not use information about medical treatments comprehensively or systematically when making treatment decisions, and their processing of medical information was biased by their previous beliefs about cancer and health. These findings have implications for the provision of informational and decisional support to men considering prostate cancer treatment.

Dietary chromium tripicolinate supplementation reduces glucose concentrations and improves glucose tolerance in normal-weight cats

The effect of dietary chromium supplementation on glucose and insulin metabolism in healthy, non-obese cats was evaluated. Thirty-two cats were randomly divided into four groups and fed experimental diets consisting of a standard diet with 0 ppb (control), 150 ppb, 300 ppb, or 600 ppb added chromium as chromium tripicolinate. Intravenous glucose tolerance, insulin tolerance and insulin sensitivity tests with minimal model analysis were performed before and after 6 weeks of feeding the test diets. During the glucose tolerance test, glucose concentrations, area under the glucose concentration-time curve, and glucose half-life (300 ppb only), were significantly lower after the trial in cats supplemented with 300 ppb and 600 ppb chromium, compared with values before the trial. Fasting glucose concentrations measured on a different day in the biochemistry profile were also significantly lower after supplementation with 600 ppb chromium. There were no significant differences in insulin concentrations or indices in either the glucose or insulin tolerance tests following chromium supplementation, nor were there any differences between groups before or after the dietary trial. Importantly, this study has shown a small but significant, dose-dependent improvement in glucose tolerance in healthy, non-obese cats supplemented with dietary chromium. Further long-term studies are warranted to determine if the addition of chromium to feline diets is advantageous. Cats most likely to benefit are those with glucose intolerance and insulin resistance from lack of exercise, obesity and old age. Healthy cats at risk of glucose intolerance and diabetes from underlying low insulin sensitivity or genetic factors may also benefit from long-term chromium supplementation. (C) 2002 ESFM and AAFP.

Comparison of an ELISA and an LC/MS/MS method for measuring tacrolimus concentrations and making dosage decisions in transplant recipients

This study compared an enzyme-linked immunosorbent assay (ELISA) to a liquid chromatography-tandem mass spectrometry (LC/MS/MS) technique for measurement of tacrolimus concentrations in adult kidney and liver transplant recipients, and investigated how assay choice influenced pharmacokinetic parameter estimates and drug dosage decisions. Tacrolimus concentrations measured by both ELISA and LC/MS/MS from 29 kidney (n = 98 samples) and 27 liver (n = 97 samples) transplant recipients were used to evaluate the performance of these methods in the clinical setting. Tacrolimus concentrations measured by the two techniques were compared via regression analysis. Population pharmacokinetic models were developed independently using ELISA and LC/MS/MS data from 76 kidney recipients. Derived kinetic parameters were used to formulate typical dosing regimens for concentration targeting. Dosage recommendations for the two assays were compared. The relation between LC/MS/MS and ELISA measurements was best described by the regression equation ELISA = 1.02 . (LC/MS/MS) + 0.14 in kidney recipients, and ELISA = 1.12 . (LC/MS/MS) - 0.87 in liver recipients. ELISA displayed less accuracy than LC/MS/MS at lower tacrolimus concentrations. Population pharmacokinetic models based on ELISA and LC/MS/MS data were similar with residual random errors of 4.1 ng/mL and 3.7 ng/mL, respectively. Assay choice gave rise to dosage prediction differences ranging from 0% to 30%. ELISA measurements of tacrolimus are not automatically interchangeable with LC/MS/MS values. Assay differences were greatest in adult liver recipients, probably reflecting periods of liver dysfunction and impaired biliary secretion of metabolites. While the majority of data collected in this study suggested assay differences in adult kidney recipients were minimal, findings of ELISA dosage underpredictions of up to 25% in the long term must be investigated further.

Tree yield and fruit minerals concentrations influence 'Hass' avocado fruit quality

To investigate the variation in quality of 'Hass' avocado fruit within an orchard, fruit were harvested at commercial maturity from 15 'Hass' trees of similar appearance, growing in three adjacent rows on the same soil type, and receiving similar management. Fruit were harvested at commercial maturity, and either ripened at 22 degreesC or stored at 2 or 7 degreesC for 3 or 5 weeks and then ripened. Significant positive correlations (based, on the mean for each datum tree) were noted between fruit flesh calcium (Ca) and magnesium (Mg) concentrations and the (Ca + Mg)/potassium ratio, and the number of days for the fruit to reach the eating ripe stage (DTR). Negative correlations were also observed between these minerals and anthracnose and mesocarp discolouration (MD) severity. Negative correlations were observed between fruit potassium (K) and phosphorus (P) concentrations and DTR. Fruit from trees with high fruit yield were generally smaller, with lower anthracnose and MD severity, ripened more slowly, and had higher flesh Ca concentrations. It is likely that cultural practices that maintain moderate to high fruit yield and reduce variation in yield will improve avocado fruit quality and reduce variability in quality. Since the main differences between adjacent trees in this trial were the seedling rootstocks of unknown origin, it is suggested that rootstocks can have a significant impact on avocado yield and fruit quality. (C) 2002 Elsevier Science B.V. All rights reserved.