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Background Marfan syndrome (MFS), a congenital connective tissue disorder leading to aortic aneurysm development, is caused by fibrillin-1 (FBN1) gene mutations. Transforming growth factor beta (TGF-β) might play a role in the pathogenesis. It is still a matter of discussion if and how TGF-β up-regulates the intracellular downstream pathway, although TGF-β receptor 3 (TGFBR3 or Betaglycan) is thought to be involved. We aimed to elucidate the role of TGFBR3 protein in TGF-β signaling in Marfan patients. Methods Dermal fibroblasts of MFS patients with haploinsufficient (HI; n=9) or dominant negative (DN; n=4) FBN1 gene mutations, leading to insufficient or malfunctioning fibrillin-1, respectively, were used. Control cells (n=10) were from healthy volunteers. We quantified TGFBR3 protein expression by immunofluorescence microscopy and gene expression of FBN1, TGFB1, its receptors, and downstream transcriptional target genes by quantitative polymerase chain reaction. Results Betaglycan protein expression in FBN1 mutants pooled was higher than in controls (P=.004) and in DN higher than in HI (P=.015). In DN, significantly higher mRNA expression of FBN1 (P=.014), SMAD7 (P=.019), HSP47 (P=.023), and SERPINE1 (P=.008), but a lower HSPA5 expression (P=.029), was observed than in HI. A pattern of higher expression was noted for TGFB1 (P=.059), FN1 (P=.089), and COL1A1 (P=.089) in DN as compared to HI. TGFBR3 protein expression in cells, both presence in the endoplasmic reticulum and amount of vesicles per cell, correlated positively with TGFB1 mRNA expression (Rs=0.60, P=.017; Rs=0.55, P=.029; respectively). TGFBR3 gene expression did not differ between groups. Conclusion We demonstrated that activation of TGF-β signaling is higher in patients with a DN than an HI FBN1 gene mutation. Also, TGFBR3 protein expression is increased in the DN group and correlates positively with TGFB1 expression in groups pooled. We suggest that TGFBR3 protein expression is involved in up-regulated TGF-β signaling in MFS patients with a DN FBN1 gene mutation.

Background: In abdominal aortic aneurysm (AAA), pathophysiology deterioration of the medial aortic layer plays a critical role. Key players in vessel wall degeneration are reactive oxygen species (ROS), smooth muscle cell apoptosis, and extracellular matrix degeneration by matrix metalloproteinase-9 (MMP-9). Lipocalin-2, also neutrophil gelatinase-associated lipocalin (NGAL), is suggested to be involved in these degenerative processes in other cardiovascular diseases. We aimed to further investigate the role of NGAL in AAA development and rupture. Methods: In this observational study, aneurysm tissue and blood of ruptured (n = 13) AAA patients were investigated versus nonruptured (n = 26) patients. Nondilated aortas (n = 5) from deceased patients and venous blood from healthy volunteers (n = 10) served as controls. NGAL concentrations in tissue and blood were measured by enzyme-linked immunosorbent assay and immunofluorescence microscopy. Nitrotyrosine (marker of ROS), MMP-9, and caspase-3 (marker of apoptosis) in aneurysm tissue were measured by immunofluorescence microscopy. AAA expansion rates were calculated retrospectively. Results: NGAL (in μg/mL) blood concentration in ruptured AAA was 46 (range 22–122) vs. 26 (range 6–55) in nonruptured AAA (P < 0.01) and 14 (range 12–22) in controls (P < 0.01). In the aneurysm wall of ruptured AAA, NGAL concentration was 4.7 (range 1.4–25) vs. 4.4 (range 0.2–14) in nonruptured AAA (not significant) and 1.8 (range 1.2–2.7) in nondilated aortas (P = 0.04). In the medial layer, NGAL correlated positively with nitrotyrosine (Rs = 0.80, P < 0.01), MMP-9 (Rs = 0.56, P = 0.02), and caspase-3 (Rs = 0.75, P = 0.01). NGAL did not correlate to AAA expansion rate in blood or tissue (P = 0.34 and P = 0.95, respectively). Conclusions: This study demonstrates that NGAL blood concentration is higher in ruptured AAA patients than in nonruptured AAA. NGAL expression in the AAA wall is also higher than in nondilated aorta. Furthermore, its expression is associated with factors of vessel wall deterioration. Based on our study results, we could not determine NGAL as a biomarker for AAA growth or rupture. However, our findings do support a potential role of NGAL in the development of AAA.

Background: Breast cancer risk is temporarily increased after a full-term pregnancy and declines thereafter, possibly due to increased levels of gonadal and placental hormones during pregnancy. Inconsistent results, however, have been reported after twin pregnancies with higher hormone levels. Among women treated with in vitro fertilisation (IVF), for whom the number of embryos available for implantation is known, we recently observed that a multiple birth after implantation of all transferred embryos is associated with higher levels of vascular endothelial growth factor (VEGF). As VEGF is involved in breast cancer progression, we studied the effects of embryo implantation and a multiple birth on breast cancer risk in a nationwide Dutch cohort of IVF-treated women. Methods: We performed a cohort analysis among 12,589 women who had been treated with IVF between 1983 and 1995 and completed a risk factor questionnaire between 1997 and 1999. Data on IVF treatment were obtained from medical records. Breast cancer cases were ascertained through linkage with the population-based Netherlands Cancer Registry. Breast cancer risks associated with singleton and multiple births were estimated with Cox regression. Findings: There were 1688 women (13.4%) with multiples, 6027 (47.9%) with singletons and 4874 (38.7%) nulliparous women. Breast cancer occurred in 317 women of whom 57 had multiples. Breast cancer risk was 1.44 times higher in mothers of multiples than in mothers of singletons (95% confidence interval (CI) 1.06-1.97). Risk was highest in women who gave birth to multiples from all embryos transferred (adjusted hazard ratio (HR) 1.86, 95% CI 1.01-3.43), and lower for those with multiples after incomplete embryo implantation (adjusted HR 1.31, 95% CI 0.76-2.25). Interpretation: A woman's potential to implant all transferred embryos may be associated with breast cancer risk. Further research is needed to confirm our results and to identify the underlying biological mechanisms. (C) 2014 Elsevier Ltd. All rights reserved.

Objectives Extensive reactive oxygen and nitrogen species (also reactive species) production is a mechanism involved in abdominal aortic aneurysm (AAA) development. White blood cells (WBCs) are a known source of reactive species. Their production may be decreased by statins, thereby reducing the AAA growth rate. Reactive species production in circulating WBCs of AAA patients and the effect of statins on their production was investigated. Methods This observational study investigated reactive species production in vivo and ex vivo in circulating WBCs of AAA patients, using venous blood from patients prior to elective AAA repair (n = 34; 18 statin users) and from healthy volunteers (n = 10). Reactive species production was quantified in circulating WBCs using immunofluorescence microscopy: nitrotyrosine (footprint of peroxynitrite, a potent reactive nitrogen species) in snap frozen blood smears; mitochondrial superoxide and cytoplasmic hydrogen peroxide (both reactive oxygen species) by live cell imaging. Neutrophils, lymphocytes, and monocytes were examined individually. Results In AAA patients using statins, the median nitrotyrosine level in neutrophils was 646 (range 422–2059), in lymphocytes 125 (range 74–343), and in monocytes 586 (range 291–663). Median levels in AAA patients not using statins were for neutrophils 928 (range 552–2095, p = .03), lymphocytes 156 (101–273, NS), and for monocytes 536 (range 535–1635, NS). The statin dose tended to correlate negatively with nitrotyrosine in neutrophils (Rs −0.32, p = .06). The median levels in controls were lower for neutrophils 466 (range 340–820, p < .01) and for monocytes 191 (range 102–386, p = .03), but similar for lymphocytes 99 (range 82–246) when compared to the AAA patients. There were no differences in mitochondrial superoxide and cytoplasmic hydrogen peroxide between statin and non-statin users within AAA patients. Conclusions It was found that the peroxynitrite footprint in circulating neutrophils and monocytes of AAA patients is higher than in controls. AAA patients treated with statins had a lower peroxynitrite footprint in neutrophils than non-statin users.

Summary. Background: Vitamin K1 (VK1) reverses the effects of vitamin K antagonists (VKAs). The literature shows that the bioavailability from solutions might be higher than that from tablets, possibly resulting in different effects. Objectives: To compare the bioavailability and effect on the International Normalized Ratio (INR) of 5-mg VK1 tablets and solution in three randomized clinical trials. Methods and results: The bioavailability was determined in a crossover trial with 25 healthy volunteers. VK1 plasma concentrations were assessed at 0, 2, 4, 5, 6, 8, 10 and 24 h, and the area under the curve was higher in the solution group than in the tablet group (mean difference 365 l gL 1 h, 95% confidence interval [CI] 230– 501, P < 0.0001). In the other two trials, the effects of both formulations on the INR were measured at 0, 24 and 48 h. In the second trial, on 72 patients on phenprocoumon with planned invasive procedures, both formulations were similarly effective, because all patients reached an INR of < 2.0, which was the primary endpoint. In the last trial, on 72 patients on phenprocoumon with an INR of 7.0–11.0, the INR decreased slightly more in the solution group (4.7, 95% CI 4.3–5.1) than in the tablet group (4.2, 95% CI 3.8–4.6). The solution group had a 3.3-fold increased likelihood (95% CI 0.7–15.1) of reaching an INR of < 2.0 at 48 h. Additionally, the increases in VK1 concentrations were similar (tablets, 3.2 l gL 1 ; solution, 3.4 l gL 1 ; P = 0.99) after 24 h. Conclusions: VK1 tablets are at least as clinically effective as the solution in countering VKAs.

For genetic evaluation of beef cattle, univariate or bivariate analyses are often performed as an alternative to decrease the complexity of matrices and mathematical models compared to multivariate analysis, which considers a larger number of joint traits. The use of bivariate methods to calculate genetic predictors may cause bias in the estimation of breeding values and, as a consequence, reclassification of the rank of top-selected sires, resulting in a loss of genetic gain in future generations. The objective of this study was to compare the bivariate and multivariate joint methods of genetic evaluation, verifying the selection loss, and reclassification of the ranking of the best animals with different selection intensities. Records of 431,224 Nellore breed animals were evaluated for birth weight, weaning weight, post-weaning gain, muscle score, scrotal circumference, and selection index. The pedigree file consisted of 505,848 animals, including 218,727 males and 287,121 females. The predicted breeding values were obtained using the program PEST 2, and the complete pedigree analysis was performed by the PopReport software. The results showed that, for the four different selection intensities considered (TOP 10 and 1, 10, and 30%), selection loss and reclassification of animals in ranking, were detected for all traits evaluated when the two methods of analysis were compared.

Study question: Does preconceptionally started low-dose aspirin prevent hypertensive pregnancy complications and preterm delivery in IVF patients? Summary answer: The current data do not support the use of preconceptionally started low-dose aspirin treatment for the prevention of hypertensive pregnancy complications and preterm delivery in IVF women. What is known already: Studies starting low-dose aspirin treatment as prevention in the second trimester of pregnancy found no or only moderate reductions in the relative risk of developing pre-eclampsia. Low-dose aspirin was possibly started too late, that is after the first episode of trophoblast invasion. Study design, size, duration: We performed a meta-analysis with individual patient data (IPD), in which four authors could provide IPD on a total of 268 pregnancies (n ¼ 131 treated with aspirin, n ¼ 137 placebo). Data on hypertensive pregnancy complications and preterm delivery were collected. Participants/materials, setting, methods: All separate databases were merged into a summary database. Treatment effect of aspirin on the incidence of hypertensive pregnancy complications (n ¼ 187) and preterm delivery (n ¼ 180) were estimated with odds ratios (OR) and 95% confidence intervals (95% CI) using multivariable logistic regression. Main results and the role of chance: There were significantly fewer twin pregnancies in the aspirin group (OR 0.55 95% CI 0.30–0.98), but no significant differences for hypertensive pregnancy complications and preterm delivery: for singletons OR 0.62 (95% CI 0.22–1.7) and OR 0.52 (95% CI 0.16–1.7), respectively, as well as for twin pregnancies OR 1.2 (95% CI 0.35–4.4) and OR 1.6 (95% CI 0.51–5.0), respectively. Limitations, reasons for caution: We have to bear in mind that the included studies showed clinical heterogeneity; there was variation in the duration of low-dose aspirin therapy and degree of hypertension between the different studies. Although we combined IPD from four studies, we have to realize that the studies were not powered for the outcome of the current IPD meta-analysis. Wider implications of the findings: Based on the current meta-analysis with IPD we found no confirmation for the hypothesis that preconceptionally started low-dose aspirin reduces the incidence of hypertensive pregnancy complications or preterm delivery in IVF women. Larger studies are warranted. Study funding/competing interest(s): None. Trial registration number: not applicable.

Open surgical repair of an aortic aneurysm requires aortic cross-clamping, resulting in temporary ischemia of all organs and tissues supplied by the aorta distal to the clamp. Major complications of open aneurysm repair due to aortic cross-clamping include renal ischemia-reperfusion injury and postoperative colonic ischemia in case of supra- and infrarenal aortic aneurysm repair. Ischemia-reperfusion injury results in excessive production of reactive oxygen species and in oxidative stress, which can lead to multiple organ failure. Several perioperative protective strategies have been suggested to preserve renal function during aortic cross-clamping, such as pharmacotherapy and therapeutic hypothermia of the kidneys. In this chapter, we will briefly discuss the pathophysiology of ischemia-reperfusion injury and the preventative measures that can be taken to avoid abdominal organ injury. Finally, techniques to minimize the risk of complications during and after open aneurysm repair will be presented.

The position of transfer air bubbles after embryo transfer is related to the pregnancy rate. With the conventional manual embryo-transfer technique it is not possible to predict the final position of the air bubbles. This position mainly depends on the catheter load speed at transfer (injection speed), a parameter that remains uncontrollable with the conventional technique even after standardization of the protocol. Therefore, the development of an automated device that generates a standardized injection speed is desirable. This study aimed to examine the variation in injection speeds in manual embryo transfer and pump-regulated embryo transfer (PRET). Seven laboratory technicians were asked to perform simulated transfers using the conventional embryo-transfer technique. Their injection speeds were compared with that of a PRET device. The results indicate that in manually performed transfers, even after standardization of the protocol, there is still a large variation in injection speed, while a PRET device generates a reliable and reproducible injection speed and therefore brings new possibilities for further standardization of the embryo-transfer procedure. Future research should reveal whether these experiments mimic real clinical circumstances and if a standardized injection speed results in more exact positioning of the transferred embryos and therefore higher pregnancy rates. The position of transfer air bubbles after embryo transfer is related to the pregnancy rate. With the currently used embryo-transfer technique, in which embryos are transferred manually with a syringe, we are not able to predict the final position of the air bubbles. This position depends on the injection speed of the syringe, which remains uncontrollable in embryo transfers that are performed manually even after standardization of the protocol. Therefore we developed an automated device that generates a reliable and reproducible injection speed, a pump-regulated embryo transfer (PRET) device. This study aimed to examine the variation in injection speeds in transfers performed manually and with the PRET device. Our results indicate that in manually performed transfers, even after standardization by protocol, there is still a large variation in injection speed and that the PRET device generates a reliable and reproducible injection speed and therefore brings new possibilities for further standardization of the embryo-transfer procedure. Future research should reveal whether our experiments mimic real clinical circumstances and if a standardized injection speed results in more exact positioning of the transferred embryos and therefore higher pregnancy rates. © 2011, Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.

To evaluate the correlation between the International Prostate Symptom Score (IPSS) and a new Visual Prostate Symptom Score (VPSS) using pictures rather than words to assess lower urinary tract symptoms (LUTS).Four IPSS questions related to frequency, nocturia, weak stream, and quality of life (QoL) were represented by pictograms in the VPSS. Men with LUTS were given the IPSS and VPSS to complete. Peak (Qmax.) and average (Qave.) urinary flow rates were measured. Statistical analysis was performed using Student's t, Fisher's exact, and Spearman's correlation tests.The educational level of the 96 men (mean age 64, range 33-85 years) evaluated August 2009 to August 2010 was school grade 8-12 (62%), grade 1-7 (28%), university education (6%), and no schooling (4%). The IPSS was completed without assistance by 51 of 96 men (53%) and the VPSS by 79 of 96 men (82%) (P.001). Comparing education grade7 vs grade10 groups, the IPSS required assistance in 27 of 31 men (87%) vs 9 of 38 men (24%) (P.001), and the VPSS required assistance in 10 of 31 men (32%) vs 3 of 38 men (8%) (P=.014). There were statistically significant correlations between total VPSS, Qmax. and Qave., total VPSS and IPSS, and individual VPSS parameters (frequency, nocturia, weak stream and QoL) vs their IPSS counterparts.The VPSS correlates significantly with the IPSS, Qmax. and Qave., and can be completed without assistance by a greater proportion of men with limited education, indicating that it may be more useful than the IPSS in patients who are illiterate or have limited education.

Aspirin is believed to improve the outcome of IVF, but previous conventional meta-analyses on the subject are conflicting. Therefore, we performed a meta-analysis with individual patient data (IPD MA) of randomized clinical trials (RCTs) on the subject. A systematic literature search was conducted to identify RCTs assessing the effectiveness of aspirin in IVF. Authors were asked to share their original data. In a one step meta-analytic approach, the treatment effect of aspirin was estimated with odds ratios (ORs) and 95% confidence intervals (CIs) using logistic regression, based on the intention to treat principle. Ten studies fulfilled the inclusion criteria. Authors of six studies provided IPD, including 1119 patients (562 placebo and 557 aspirin). There were 160 clinical pregnancies in the aspirin (28.8%) and 179 (31.9%) in the placebo group [OR 0.86, 95% CI (0.69-1.1)]. There were 129 ongoing pregnancies in the aspirin (23.6%) and 147 in the placebo group (26.7%) [OR 0.85, 95% CI (0.65-1.1)]. Whereas the conventional meta-analysis limited to studies that could provide IPD showed an OR of 0.89 (95% CI 0.69-1.2), the conventional meta-analysis limited to the eight studies of which method of randomization could be confirmed showed an OR of 0.94 (95% CI 0.76-1.17) and the conventional meta-analysis including all 10 eligible RCTs identified with our search changed the OR to 1.07 (95% CI 0.81-1.41). This difference in direction of effect, derived from the studies not able to share IPD of which quality of randomization could not be confirmed. Aspirin does not improve pregnancy rates after IVF

The objective of this study was to identify and quantify the influence of F (inbreeding coefficient) on weaning weight (WW), weight gain from weaning to 18 months of age (WG345), finishing visual score (precocity) at 18 months of age, muscling visual score at 18 months of age (MUS), hip height (HH), scrotal circumference at 18 months of age (SC), heifer probability of pregnancy at 14 months of age (PP14), and stayability (STAY) in Brazilian Nellore cattle. The complete pedigree included 417,552 animals born between 1984 and 2007 on 12 farms located in the states of Mato Grosso do Sul, Sao Paulo and Bahia. Following the observation of a statistically significant effect ( P F ) and maternal inbreeding coefficient, regression analysis of each trait, adjusted for all other effects, was performed as a function of the linear and quadratic effect of F and maternal F (when significant). Inbreeding negatively affected all traits studied ( P F on WW, WG345, HH and PP14, and a quadratic effect of maternal F on WG345 and HH were observed. Levels of inbreeding higher than 7–11% affected negatively growth and reproductive performance of Nellore cattle. Therefore, inbreeding should be avoided, except for purposes of genetic breeding whose main objective is the fixation of certain alleles in the population.

In recent years the nature of HIV infection has been dramatically transformed from an invariably fatal disease to a chronic disorder with a relatively benign course. Disease progression from HIV to AIDS and HIV-related mortality can be reduced effectively by several years of treatment with highly active antiretroviral therapy (HAART). For patients who do not have access to HAART, HIV infection continues to be a lethal disorder characterized by opportunistic infection with uncommon organisms (e.g. mycobacteria, fungi, parasites and viruses), as well as lethal malignancies such as Kaposi sarcoma, non-Hodgkin lymphoma and squamous cell carcinoma of the penis or cervix. In patients receiving HAART, urologic complications are likely to be caused by adverse effects of antiretroviral medication (e.g. indinavir urolithiasis) or disorders associated with aging, such as benign prostatic hyperplasia and prostate cancer. Prospective clinical trials have shown that adult male circumcision can reduce the rate of female to male HIV transmission by more than 50%; however, the development of preventive or curative modalities with 100% efficacy remains elusive.

Data from about 2900 litters (approximately 40,000 piglets) originating from 1063 Czech Large White hyperprolific sows were analyzed. The phenotypic and genetic relations between litter size traits, piglet mortality during farrowing and from birth to weaning and several statistics referring to the distribution of the birth weight within litter were analyzed. All genetic parameters were estimated from multi-trait animal models including the following factors: mating type (natural service or insemination), parity, linear and quadratic regression on age at first farrowing (1 st litter) or farrowing interval (2nd and subsequent litters), herd-year-season effect and additive-genetic effect of the sow. The phenotypic correlations of the mean birth weight with the total number of piglets born and piglets born alive were - 0.30. Traits describing the variability of the birth weight within litter (range, variance, standard deviation, coefficient of variation) were mostly positively correlated with litter size. A statistically significant phenotypic correlation (- 0.09 to - 0.15) between mean birth weight and losses at birth and from birth to weaning was found. The heritability for the number of piglets born, piglets born alive and piglets weaned was around 0.15. The number of stillborn piglets bad only a very low heritability less than 0.05, whereas the heritability for losses from birth to weaning was 0.13. The heritabilities of the mean, minimal and maximal birth weight were 0.16, 0.10 and 0.10, respectively. The heritability for all statistics and measures referring to the variability of the birth weight within litter was very low and did never exceed the value of 0.05. An increase in litter size was shown to be genetically connected with a decrease in the mean piglet birth weight and an increase in the within-litter variability of birth weight. Selection on litter size should be accompanied by selection on mortality traits and/or birth-weight traits. Losses from birth to weaning and the minimal birth weight in the litter were proposed as potential traits for a selection against piglet mortality. (C) 2007 Elsevier B.V. All rights reserved

Background/Aims: Catheter injection speed affects depth and placement of the embryo into the uterine cavity and is shown to be highly variable in, and between, subjects in a manually performed embryo transfer. In an effort to standardize the injection speed during embryo transfer, we developed an automated transfer pump: the pump-regulated embryo transfer (PRET) device. In this randomized controlled trial, we aimed to investigate if standardization of the injection speed and pressure with this PRET results in a better controlled positioning of the transferred embryo(s). Methods: Five hundred ninety-nine in-vitro fertilization/intracytoplasmic sperm injection/frozen-thawed embryo transfer cycles were randomly assigned to the PRET or manual transfer. Positioning of the embryo(s) into the uterine cavity was measured with ultrasound. Results: The PRET device generates a significantly smaller variance of the positioning of the embryo(s) into the uterine cavity. This resulted in an ongoing pregnancy rate of 21% in the PRET versus 17% in the manual (p = 0.22) transfer group; frozen-thawed embryo transfers resulted in 17.5 versus 10.9% (p = 0.097), respectively. Conclusion: The PRET results in better controlled positioning of the embryo(s), and it also gives the opportunity to standardize embryo transfer. Whether the PRET may positively influence pregnancy rates, needs to be investigated in a multicenter trial.

BACKGROUND: Extracellular matrix degeneration, caused by matrix metalloproteinase-2, facilitates smooth muscle cell migration leading to medial layer decline and, ultimately, abdominal aortic aneurysm. It remains unclear what exactly causes aneurysms to rupture, which leads to death in most patients. The extracellular signal-related kinase may be linked to the latter process. We aimed to clarify the role of extracellular signal-related kinase in aortic aneurysm development and rupture in patients.DESIGN: Aortic fragments were harvested during open repair of nonruptured (n = 20) and ruptured (n = 8) aneurysms. As control, nondilated aortas (n = 6) were obtained during autopsy. We determined levels of phosphorylated and total extracellular signal-related kinase by Western blot, matrix metalloproteinase-2 by immunohistochemistry and medial layer thickness by conventional microscopy.RESULTS: Nonruptured aneurysms had 1·8 times higher activation of extracellular signal-related kinase (ratio: phosphorylated/total) than controls (P = 0·011). However, the ruptured aneurysms had only 0·9 times the activation of controls (ns). Both nonruptured and ruptured aneurysms showed significantly higher matrix metalloproteinase-2 than controls (3·8 and 4·0-times, respectively; P < 0·005). Of the medial layer thickness in controls, the median was 1·5 mm, in nonruptured 1·0 mm and in ruptured aneurysms 0·7 mm. Activation of extracellular signal-related kinase correlated positively to medial layer thickness (Rs = 0·48; P = 0·014), but not to matrix metalloproteinase-2 (Rs = -0·36; P = 0·10).CONCLUSIONS: In this study, nonruptured aneurysms are associated with increased extracellular signal-related kinase activation while ruptured aneurysms are not. Extracellular signal-related kinase was not related to total matrix metalloproteinase-2 expression. We therefore speculate that increased extracellular signal-related kinase, in response to medial layer decline, could be protective against aneurysm rupture.

The data sets consisted of field performance data from 54 848 purebred and 16 175 crossbred animals (Czech data set, CZ) and 16 610 purebred and 9 228 crossbred animals (Slovak data set, SK). Animals from the following breeds were included: Duroc, Hampshire, Piétrain, sire line of Large White (CZ) or Yorkshire (SK), Czech Meat pig (CZ) or Slovak Meat pig (SK), Belgian Landrace (SK). Two-trait animal models were calculated for average daily gain from birth to the end of the field test (ADG) and lean meat content (LM, only in CZ) or backfat thickness (BF, only in SK). The models included additive breed and breed heterotic effects. Piétrain was the breed with the highest LM and the lowest BF. The additive genetic breed effect was about 1·5% LM (CZ) in comparison with Large White or −0·4 mm BF (SK) in comparison to Yorkshire. The sire line of Large White (CZ) or the Yorkshire breed (SK) clearly exceeded all the remaining sire breeds in ADG (on average by 30 to 50 g/day). There was a clear tendency to negative heterosis in LM in all crossbred combinations (CZ). In BF, heterotic effects between −0·2 mm and +0·3 mm were estimated, mostly not being significant (SK). The estimates of the heterotic effects for ADG were positive throughout. Higher values up to 40 g/day (7%) were observed in the Czech data set. Though heterotic breed effects are of some importance especially for ADG, their inclusion in the equations for breeding value estimation will have only a minor impact on the predicted breeding values.

SummaryIn response to the rapid loss of animal genetic resources, a world wide emergency program is proposed to create national genebanks on the basis of somatic cells. Contrary to other procedures, like storing deep frozen semen or embryos, collection and storage of somatic cells can be done cheaply and rapidly for any species. Only in this way can an emergency store of animal genetic resources be created fast enough to forestall the ongoing rapid erosion of animal biodiversity. While animals can already be produced from somatic cells for 10 species, this number will continue to rise in the future. A layered strategy is proposed which is based on collection and storage within individual countries, thus leaving execution of the program, responsibility and ownership of these national cryobanks with those countries. After a pilot study, more country genebanks could be created as funds become available. With a limited effort, the creation of a network of national genebanks of last resort are a realistic option.

Covariance matrices and genetic parameters for milk production traits in sheep were estimated for the Improved Valachian and Tsigai breeds. These multipurpose breeds are of local importance, and are bred for milk, meat and wool. The traits under study were daily milk yield and fat and protein content. Genetic analyses were based on test-day records gathered over the period from 1995 to 2001. Each breed was analyzed separately. Only purebred animals with at least four test days per lactation were considered. The data set for the Improved Valachian consisted of 117,959 test-day records of 28,753 lactations belonging to 18,867 ewes. The corresponding pedigree comprised information on 32,804 animals. For the Tsigai breed, the data set consisted of 52,191 test-day records of 12,382 lactations belonging to 8,132 ewes and the pedigree comprised 14,576 animals. The three-trait animal model was used for analyses. To account for different lactation stage, a fixed regression on individual test days was employed. In addition to the function describing, effects of days in milk, effects of lactation, litter size, number of milkings per day, age at lambing, and flock-test day as well as additive genetic and permanent environmental effect of the animal were included in the model. Of these, flock-test day, additive genetic and permanent environmental effects were treated as random. Restricted maximum likelihood (REML) algorithm was used to estimate genetic parameters and covariance matrices. Heritabilities were 0.10 and 0.19 for daily milk yield, 0.06 and 0.12 for fat content, 0.07 and 0.17 for protein content for the Improved Valachian and Tsigai breeds, respectively. Genetic correlations between milk yield and fat content for the two breeds were −0.29 and −0.23 and those between milk yield and protein content were −0.30 and −0.27. Genetic correlations between fat and protein content were 0.58 and 0.57. Higher values (either positive or negative) were found for the breed with the larger number of records. Variance ratios and correlations were also estimated for nongenetic effects for both breeds. Variance ratios for the flock-test-day effects were rather high, ranging from 0.34 to 0.48. Higher values for these effects were found in the Improved Valachian sheep, reflecting more variability in management conditions in this breed. The genetic parameters estimated in this study should be used in routine genetic evaluation of milk production traits of local sheep breeds to replace present selection criteria based on phenotype values of dam milk yield.

SummaryIn order to study the role of the asialoglycoprotein receptor (ASGPr) in the rapid plasma clearance of urokinase-type plasminogen activator (u-PA), a microtiter plate binding assay was developed using ASGPr purified from rat liver extracts. Urinary two-chain u-PA bound to immobilized ASGPr in a saturable manner with an EC50 of 0.2 µM. Binding was inhibited by rabbit antibodies against the ASGPr. In line with the known carbohydrate specificity of the ASGPr, GalNAc proved to be the most effective inhibitor from a series of monosaccharides, followed by Gal and Fuc, whereas GlcNAc was ineffective. The N-linked oligosaccharides of urinary u-PA do not terminate with the common Gal-GlcNAc element, but with a GalNAc-GlcNAc element which is partially sulfated. Sulfated forms of u-PA were separated from non-sulfated forms by using the lectin Wisteria floribunda agglutinin. Only the non-sulfated forms of u-PA (30% of the total) appeared to bind to the ASGPr. From different u-PA preparations used for thrombolytic therapy only urinary u-PA and u-PA produced by kidney cell cultures strongly bound to the ASGPr, whereas (recombinant) u-PA expressed in mouse myeloma cells, Chinese hamster ovary cells or E. coli scarcely bound to the receptor. It is concluded that u-PA bearing non-sulfated GalNAc-GlcNAc elements is specifically recognized by the ASGPr present on liver cells.

The complete covariance structure for the traits birth, weaning (WW), yearling (YW), and final weight was estimated in Afrikaner beef cattle, which is indigenous to the Republic of South Africa. Fifty-seven (co)variance components were estimated simultaneously in a four-trait model. Direct heritabilities for the four traits were: 0.52, 0.23, 0.17 and 0.17, while those for the maternal components were 0.07, 0.13, 0.06 and 0.03. Genetic correlations among the traits were high among adjacent traits, and particularly high with 0.93 between WW and YW for the direct component and 0.96 between WW and YW for the maternal component.

Data from 69,525 animals were used to compare two types of analyses, one of them having the weaning management group (WEMANG) included as an effect in the contemporary group (F_WEMANG) and the other considering the weaning management group as a random effect, not related to the mathematical model (R_WEMANG) for post-weaning traits. The components of (co)variance were estimated for pre-weaning traits (birth weight and weaning weight) and for post-weaning traits [scrotal circumference (SC), weight gain from weaning to 18 months of age (WG) and muscle score (MUSC)] in Nellore cattle, based on a complete animal model. Heritability of SC, WG and MUSC for the F_WEMANG model was equal to 0.46 ± 0.02, 0.38 ± 0.03 and 0.26 ± 0.01, and for the R_WEMANG model it was 0.45 ± 0.02, 0.31 ± 0.03 and 0.25 ± 0.01, respectively. Genetic correlations between all the studied traits varied between 0.07 ± 0.01 and 0.77 ± 0.03 in F_WEMANG and between 0.02 ± 0.01 and 0.76 ± 0.04 in R_WEMANG. The R_ WEMANG model allowed a decrease in the number of contemporary groups as well as an increase in the number of observations per group without significant alterations in heritability coefficients, for the post-weaning traits. Consequently, the analysis became more robust and avoided having contemporary groups with low variability.

OBJECTIVE: To study the incidence of different histological types of bladder cancer in various racial groups living within the same geographical region. PATIENTS AND METHODS: The study included 615 new patients with bladder cancer seen at three Provincial hospitals in Durban from January 1980 to January 1990. The patients were classified as Caucasian (white people of European descent). African (indigenous black people), Asian (people originating from the Indian subcontinent) or Coloured (people of mixed race). The bladder tumours were classified according to standard histopathological criteria as transitional cell carcinoma, adenocarcinoma or sarcoma. Mixed tumours consisted of both carcinomatous and sarcomatous or undifferentiated elements. RESULTS: Transitional cell carcinoma constituted 95% of the cancers in Caucasians, compared with only 30% in Africans, whereas squamous cell carcinoma occurred in 53% of the African patients, but in only 2% of the Caucasians. In Asian patients, 75% of the tumours were transitional cell and 18% were squamous cell carcinoma, whereas in Coloureds 82% were transitional cell and 9% squamous cell carcinoma. Undifferentiated carcinoma occurred in 8% of African and only 1% of Caucasian patients, whereas adenocarcinoma, mixed tumours and sarcoma occurred in 9% of African patients and only 2% of Caucasian patients. Ova of Schistosoma haematobium were seen in microscopic sections of the bladder tumour in 85% of the patients with squamous cell carcinoma, in 50% of those with undifferentiated tumours and adenocarcinoma, in 17% of those with mixed tumours or sarcoma, and in only 10% of the patients with transitional cell carcinoma. At presentation, African patients were a mean of > 20 years younger than Caucasians. In African patients with squamous cell carcinoma, 90% had stage T3 or T4 disease at presentation, whereas in Caucasian patients with transitional cell carcinoma 76% had stage T1 or T2 disease at presentation. From the study group, it appears that bladder cancer is about six times more common in Caucasians than in Africans. However, the value for Caucasian patients with bladder cancer probably underestimates the true value by about five times, so that bladder cancer in the greater Durban area may be as much as 30 times more common in Caucasians than in Africans. CONCLUSION: In African patients, endemic Schistosomiasis appears to be related to a high incidence of not only squamous cell carcinoma, but also undifferentiated tumours and adenocarcinoma of the bladder. The effective management of squamous cell carcinoma of the bladder in African patients will depend on the eradication of Schistosomiasis and the early detection of bladder cancer at a stage when it may still be cured by radical treatment.

SummaryThe recognition systems mediating the clearance of glycosylated high molecular weight single-chain urokinase-type plasminogen activator (HMW-scu-PA, produced in human embryonic kidney cells) and recombinant non-glycosylated scu-PA (rscu-PA, produced in E. coli) were analyzed by studying their binding charactaristics to freshly isolated rat parenchymal liver cells.The binding of 125I-HMW-scu-PA at 4° C was calcium-dependent and of high affinity (Kd = 37.6 nM) and could be inhibited by low molecular weight two-chain u-PA (LMW-tcu-PA) and lactose, but not by the low density lipoprotein receptor-related protein (LRP)-associated 39-kDa protein (RAP), rscu-PA or a mutant form lacking amino acids 11-135 (Delta 125-rscu-PA). Removal of the carbohydrate side chain of HMW-scu-PA by treatment with N-glycosidase F, completely reduced the specific binding to the parenchymal cells and strongly reduced its competition with 125I-HMW-scu-PA in cell binding.Recombinant scu-PA also bound with high affinity (Kd= 38.7 nM) to the parenchymal liver cells. The binding of 125I-rscu-PA could be competed for by unlabeled rscu-PA while Delta 125-rscu-PA, LMW-tcu-PA or lactose were ineffective. In contrast to HMW-scu-PA, binding of 125I-rscu-PA could be effectively inhibited by RAP (Ki = 1.1 nM), while also its association and degradation, as determined at 37° C, were inhibited by RAP. Pretreatment of the parenchymal cells with proteinase K supplied further evidence for the involvement of two different receptor systems. The binding of rscu-PA was decreased for 91%, while that of HMW-scu-PA showed a decrease of 51%.It is suggested that native HMW-scu-PA is bound and degraded by the rat parenchymal liver cells via a lectin-like recognition site, while non-glycosylated recombinant scu-PA is bound and degraded by rat parenchymal liver cells via the low density lipoprotein receptor-related protein (LRP). The differences in recognition system for native and recombinant proteins by liver cells suggest that the glycosylation of recombinant proteins, as obtained in mammalian expression systems, can be important for their physiological fate and their pharmacological application.

L'estimation du maximum de vraisemblance restreinte (REML) des composantes de variance-covariance a l'aide des procedures numeriques d'optimisation Simplex-Descendant (SD) ou quasi-Newton (QN) se heurte a la difficulte resultant de la production de matrices de covariances non definies. Jusqu'a present, cette difficulte a ete resolue en attribuant une vraisemblance arbitrairement mauvaise a de telles matrices, de facon a eviter de revenir dans cette meme direction dans les etapes suivantes d'optimisation. Dans une certaine mesure, la procedure SD est capable de faire face a cette situation, mais la procedure QN ne converge plus lorsque cette situation se reproduit trop souvent. Cette note propose un reparametrage pour resoudre le probleme. Il devient ainsi possible d'utiliser la procedure QN dont la convergence est rapide et la robustesse assuree. Quatre fichiers de donnees ont ete analysees pour estimer simultanement de 17 a 30 composantes de (co)-variance. L'optimisation du facteur de Cholesky au lieu des composantes elles-memes reduit le temps de calcul d'un facteur compris entre 2,5 et plus de 500, quand on compare la procedure QN avec reparametrage des matrices de covariance a la procedure SD modifiee appliquee aux matrices de covariance d'origine

BM 06.022 is a non-glycosylated mutant of human tissue-type plasminogen activator (t-PA) comprising only the kringle-2 and proteinase domains. The in vivo half-life of BM 06.022 antigen is 4- to 5-fold longer than that of t-PA antigen. The in vitro half-life of the activity of BM 06.022 at therapeutic concentrations in plasma is shorter than that of t-PA. In this study the inactivation of BM 06.022 in plasma was further investigated. Varying concentrations of BM 06.022 were incubated in plasma for 0-150 min. Activity assays on serial samples showed a dose-dependent decline of BM 06.022 activity with a half-life from 72 min at 0.3 μg/ml to 38 min at 10 μg/ml. SDS-polyacrylamide gel electrophoresis (SDS-PAGE) followed by fibrin autography showed the generation of several BM 06.022-complexes. These complexes could be completely precipitated with antibodies against C1-inactivator, α2-antiplasmin and α1-antitrypsin. During the incubation of BM 06.022 in plasma, plasmin was generated dose-dependently as revealed by varying degrees of α2-antiplasmin consumption and fibrinogen degradation. SDS-PAGE and immunoblotting showed that single-chain BM 06.022 was rapidly (i.e. within 45 min) converted into its two-chain form at concentrations of 5 μg/ml BM 06.022 and higher. In conclusion, BM 06.022 at therapeutic concentrations in plasma was inactivated by C1-inactivator, α2-antiplasmin and α1-antitrypsin. The half-life of the activity decreased at increasing BM 06.022 concentrations, probably as a result of the generation of two-chain BM 06.022 which may be inactivated faster than the single-chain form. Chemicals/CAS: alpha 1 antitrypsin, 9041-92-3; alteplase, 105857-23-6; fibrinogen, 9001-32-5; plasmin, 9001-90-5, 9004-09-5; reteplase, 133652-38-7; tissue plasminogen activator, 105913-11-9; proteinase inhibitor, 37205-61-1; BM 06.022; Fibrinolytic Agents; Protease Inhibitors; Recombinant Proteins; Tissue Plasminogen Activator, EC 3.4.21.68

A visual prostate symptom score (VPSS) compared with the international prostate symptom score (IPSS) for evaluation of lower urinary tract symptoms (LUTS) can be completed without physician assistance by a significantly larger proportion of men with limited education. We aimed to evaluate the correlation of the VPSS and IPSS with uroflowmetry parameters.Men with LUTS were requested to complete the IPSS and VPSS, consisting of pictograms to evaluate urinary frequency, nocturia, force of the stream and quality of life. The maximum (Qmax) and average urinary flow rate (Qave), voided volume (VV) and post-void residual (PVR) urine volumes were measured. Statistical analysis was performed using the Mann-Whitney and Spearman's tests.The study included 93 men (mean age 64 years, range 33 - 85), with VV150 ml in 66 (71%) and150 ml in 27 (29%) subjects. In the group with VV150 ml there were significant negative correlations between the IPSS and Qmax (r=-0.30, p=0.016), the IPSS and Qave (r=-0.29, p=0.018), the VPSS and Qmax (r=-0.38, p0.002) and the VPSS and Qave (r=-0.37, p0.003). The VPSS question on the subject's assessment of his urinary stream showed a significant negative correlation with the Qmax (r=-0.37, p=0.002) and Qave (r=-0.31, p=0.011), but the IPSS question on the subject's urinary stream did not correlate significantly with the Qmax or Qave.The VPSS is equivalent to the IPSS in terms of correlation with Qmax and Qave and can therefore be used instead of the IPSS to evaluate LUTS in men with limited education.

Objective In assisted reproductive techniques it is important to find a balance between high pregnancy and acceptable multiple pregnancy rates. In IVF treatment, stimulation with highly purified human menopausal gonadotropin (hMG) results in comparable or even higher pregnancy rates at lower oocyte yields compared to recombinant FSH. Since highly purified hMG contains LH activity, a number of the advantages of highly purified hMG may be attributed to this LH activity. In IUI treatment the effectiveness of highly purified hMG has been barely investigated. The aim of this study was to examine the effectiveness of highly purified hMG in IUI patients treated with a mild stimulation protocol. Study design In this retrospective study 378 patients were included, receiving 1400IUI cycles between January 2006 and December 2007. Patients were first treated with three subsequent natural cycles without controlled ovarian hyperstimulation, followed by three subsequent cycles stimulated with highly purified hMG. Primary outcomes were ongoing pregnancy rate and multifollicular growth. Secondary outcomes were multiple pregnancy and miscarriage rates. Primary and secondary outcomes were expressed in percentages with associated 95% confidence intervals (95%CI). Differences in the outcomes between natural and stimulated cycles were calculated using χ 2 tests. Statistical differences were determined at P . 05. Results Ongoing pregnancy rates increased from 6% (95%CI 4.7–7.7) per natural cycle to 7.4% (95%CI 5.2–10.3) per highly purified hMG stimulated cycle ( p =0.34). The highest ongoing pregnancy rate was observed in the fifth treatment cycle (10.8% (95%CI 6.6–17)), which is significantly higher than the ongoing pregnancy rate in the unstimulated group ( p =0.03). In the highly purified hMG group three (9.7% (95%CI 3.3–24.9)) of the ongoing pregnancies were twin pregnancies, in the unstimulated group there was one (1.7% (95%CI 0.3–9.0)) twin pregnancy ( p =0.08). Conclusion Our results indicate that mild stimulation with highly purified hMG in IUI treatment results in an acceptable balance between ongoing and multiple pregnancy rates. Future prospective trials should compare mild stimulation protocols to protocols directly starting with controlled ovarian hyperstimulation. Furthermore, these trials should compare other types and dosages of gonadotropins.

On the basis of data originating from producers and users in the swine production industry, the structure of a comprehensive information system (IS) is proposed that should cover the information needs of all participants in the process. Some present-day computer/record keeping systems are outlined and their limitations pointed out. From considerations of the scope of a comprehensive IS, it is concluded that the resultant topology of an IS calls for on-farm computers handling all data originating and pertaining to their respective locations and a central system which stores all data from every participant. The central database of identical structure contains all peripheral data as copy of the onfarm database. Also, the same operating system is run throughout the network. The information system is run functionally as a distributed database. The ensuing problems connected with redundant central storage of data are evaluated leading to the development of a high-level telecommunication protocol. A telecommunication strategy developed and implemented in the context of a distributed herdbook management system is presented from the perspective of a system designer and discussed in relation to the problems in an open information system in pig production. Its limitations are pointed out leading to a telecommunication strategy based on UNIX and international standards.

BACKGROUND: The use of aspirin during in vitro fertilization (IVF) has been investigated for its effect on pregnancy rates after IVF. In most of these studies, aspirin administration was then prolonged throughout the first trimester of pregnancy. By inhibiting vasoconstriction, the use of low-dose aspirin in the first trimester could influence placentation and therefore prevent or delay development of hypertensive pregnancy complications, such as pregnancy-induced hypertension (PIH) and pre-eclampsia (PE). METHODS: This study involved the follow-up by questionnaires and hospital records of patients with an ongoing pregnancy in a prospective, randomized, double-blind, placebo-controlled trial on the effect of low-dose aspirin during IVF. Aspirin treatment was continued throughout the first trimester of pregnancy. The primary end-point of this follow-up study was the incidence of pregnancy complications. The original trial is registered with the Dutch Trial Register and as an International Standard Randomized Clinical Trial, No. ISRNCTM97507474. RESULTS: There were 54 patients who had ongoing pregnancies in the original trial; 90.7% returned the questionnaire and all Dutch hospital records were retrieved. A significant difference was found in the incidence of hypertensive pregnancy complications: 3.6% in the aspirin group and 26.9% in the placebo group (P < 0.05), resulting in numbers-needed-to-treat (NNT) of 10.3 to prevent hypertensive complications in one pregnancy after IVF treatment. CONCLUSIONS: The incidence of hypertensive complications was significantly lower in the group of women treated with low-dose aspirin throughout IVF treatment and first trimester of pregnancy. These results suggest a potential benefit of low-dose aspirin during IVF and first trimester to prevent hypertensive pregnancy complications. The findings justify further investigation in placebo-controlled randomized trials.

Prior to implementing any information system (IS), decisions have to be made about the basic software and hardware to be used. The choices greatly influence efficiency of implementation and future flexibility. Strategic goals developed are: hardware independence, future viability, expendability, operational safety, efficiency of programming and maintenance, and end-user evaluation. Choices are discussed on the basis of the established goals. As a result, a relational database was chosen. Application development was done using high-level tools, based on the non-procedural language SQL. With the rapid development of hardware over the last year, it is now possible to run to operating system UNIX on hardware in the PC class. This allows the use of a uniform and open operating system and identical application software on all computer systems irrespective of their size, ranging from personal computers to supercomputers.

In response to the rapid loss of animal genetic resources, a world wide emergency program is proposed to create national genebanks on the basis of somatic cells. Contrary to other procedures, like storing deep frozen semen or embryos, collection and storage of somatic cells can be done cheaply and rapidly for any species. Only in this way can an emergency store of animal genetic resources be created fast enough to forestall the outgoing rapid erosion of animal biodiversity. While animals can already be produced from somatic cells for 10 species, this number will continue to rise in the future. A layered strategy is proposed which is based on collection and storage within individual countries, thus leaving execution of the program, responsibility and ownership of these national cryobanks with those countries. After a pilot study, more country genebanks could be created as funds become available. With a limited effort, the creation of a network of national genebanks of last resort are a realistic option., Zbog naglog gubitka životinjskih genetskih resursa nužan je globalni program za stvaranje banaka gena na temelju somatskih stanica. Za razliku od drugih postupaka kao što je spremanje duboko zamrznutog sjemena ili embrija, skupljanje i spremanje somatskih stanica bilo koje vrste može se obaviti jeftino i brzo. Jedino se na taj način može stvoriti nužna zaliha životinjskih genetskih resursa dovoljno brzo da se zaustavi trenutno naglo propadanje životinjske bioraznolikosti. Već sada se može proizvesti iz somatskih stanica 10 vrsta životinja a taj će broj i dalje rasti u budućnosti. Predlaže se postupna strategija koja se temelji na prikupljanju i spremanju u pojedinim zemljama i tako ostavlja izvršenje programa, odgovornost i vlasništo tih nacionalnih cryobanaka tim zemljama. Nakon pilot studije može se stvoriti više banaka gena u zemljama prema dostupnim fondovima. Ograničenim trudom stvaranje mreže nacionalnih banaka gena realan je izbor.

Methodology has been developed to implement testday models in the national genetic evaluation of dairy breeds for production traits in South Africa. Positive definite covariance matrices have been estimated, using multitrait, multi-lactation, fixed regression testday BLUP animal models, including testday records of the first three lactations as repeated measures for the Holstein and Jersey breeds. Heritability estimates were 0.40 + 0.007 for milk yield, 0.25 + 0.006 for butterfat yield and 0.37 + 0.006 for protein yield for the Holstein breed and 0.39 + 0.004 for milk yield, 0.21 + 0.002 for butterfat yield and 0.34 + 0.002 for protein yield for the Jersey breed. These estimates are well in the range of estimates reported by countries participating in INTERBULL evaluations. South African Journal of Animal Science Supp 2 2004: 35-37

Two fixed regression testday models were applied for variance component estimation and prediction of breeding values for somatic cell score, using testday records of the first three lactations of South African Holstein and Jersey cows. The first model (ML-model) considered the testdays of the different lactations as different traits in a multiple-trait animal model and the second analysis (RM-model) treated later lactation records as repeated measures of the first lactation. Heritabilities from the RM-model were more in the range of literature estimates compared to that of the ML-model, i.e. 0.19 + 0.003 for the Holstein breed and 0.18 + 0.003 for the Jersey breed. Rank correlations indicated that minor changes occur in the ranking of proven sires between breeding values obtained from the ML- and RM-models. Although genetic correlations between parities are not unity, the RM-model estimates more competitive variances and requires extensively less computer time to predict breeding values compared to the ML-model and are therefore recommended for breeding value estimation on a national basis. South African Journal of Animal Science Supp 2 2004: 32-34

Item does not contain fulltext Mercaptopurines have been used as anticancer agents for more than 40 years, and most acute lymphoblastic leukemias are treated with 6-mercaptopurine (6MP) or 6-thioguanine (TG). Overexpression of the two related multidrug resistance proteins MRP4 and MRP5 has been shown to confer some resistance against mercaptopurines, which has been attributed to extrusion of mercaptopurine metabolites by these transporters. We have analyzed the mercaptopurine metabolites formed in human embryonic kidney cells and determined which metabolites are extruded by MRP4 and MRP5. Incubation with 6MP led to the formation of thioinosine and thioxanthosine metabolites and we found that thio-IMP was transported by both MRP4 and MRP5; MRP5 showed the highest transport rate. In contrast, only MRP5 transported thioxanthosine monophosphate (tXMP). During incubation with TG, the monophosphorylated form of thioguanosine was transported by both MRP4 and MRP5; the highest transport rate was for MRP4. Similarly, only 6-methyl-thio-IMP was formed during incubation with 6-methyl mercaptopurine riboside. This compound was a substrate for both MRP4 and MRP5; MRP4 showed the highest transport rate. Our results show that all major thiopurine monophosphates important in the efficacy of mercaptopurine treatment are transported by MRP4 and MRP5, although the substrate specificity of the two transporters differs in detail.