PBDE-47 and PBDE mixture (DE-71) toxicities and liver transcriptomic changes at PND 22 after in utero/postnatal exposure in the rat.

Pentabromodiphenyl ethers (PBDE) are found in human tissue, in household dust, and in the environment, and a particular concern is the potential for the induction of cancer pathways from these fat-soluble persistent organic pollutants. Only one PBDE cancer study has been conducted and that was for a PBDE mixture (DE-71). Because it is not feasible to test all PBDE congeners in the environment for cancer potential, it is important to develop a set of biological endpoints that can be used in short-term toxicity studies to predict disease outcome after long-term exposures. In this study, PBDE-47 was selected as the test PBDE congener to evaluate and compare toxicity to that of the carcinogenic PBDE mixture. The toxicities of PBDE-47 and the PBDE mixture were evaluated at PND 22 in Wistar Han rat (Crl: WI (Han)) pups after in utero/postnatal exposure (0, 0.1, 15, or 50 mg/kg; dams, GD6-21; pups, PND 12-PND 21; oral gavage daily dosing). By PND 22, PBDE-47 caused centrilobular hypertrophy and fatty change in liver, and reduced serum thyroxin (T4) levels; similar effects were also observed after PBDE mixture exposure. Transcriptomic changes in the liver included induction of cytochrome p450 transcripts and up-regulation of Nrf2 antioxidant pathway transcripts and ABC membrane transport transcripts. Decreases in other transport transcripts (ABCG5 & 8) provided a plausible mechanism for lipid accumulation, characterized by a treatment-related liver fatty change after PBDE-47 and PBDE mixture exposure. The benchmark dose calculation based on liver transcriptomic data was generally lower for PBDE-47 than for the PBDE mixture. The up-regulation of the Nrf2 antioxidant pathway and changes in metabolic transcripts after PBDE-47 and PBDE mixture exposure suggest that PBDE-47, like the PBDE mixture (NTP 2016, TR 589), could be a liver toxin/carcinogen after long-term exposure.

Carcinogenic activity of pentabrominated diphenyl ether mixture (DE-71) in rats and mice.

Pentabrominated diphenyl ether (PBDE) flame retardants have been phased out in Europe and in the United States, but these lipid soluble chemicals persist in the environment and are found human and animal tissues. PBDEs have limited genotoxic activity. However, in a 2-year cancer study of a PBDE mixture (DE-71) (0, 3, 15, or 50 mg/kg (rats); 0, 3, 30, or 100 mg/kg (mice)) there were treatment-related liver tumors in male and female Wistar Han rats [Crl:WI(Han) after in utero/postnatal/adult exposure, and in male and female B6C3F1 mice, after adult exposure. In addition, there was evidence for a treatment-related carcinogenic effect in the thyroid and pituitary gland tumor in male rats, and in the uterus (stromal polyps/stromal sarcomas) in female rats. The treatment-related liver tumors in female rats were unrelated to the AhR genotype status, and occurred in animals with wild, mutant, or heterozygous Ah receptor. The liver tumors in rats and mice had treatment-related Hras and Ctnnb mutations, respectively. The PBDE carcinogenic activity could be related to oxidative damage, disruption of hormone homeostasis, and molecular and epigenetic changes in target tissue. Further work is needed to compare the PBDE toxic effects in rodents and humans.

[Tutankhamun: evidence-based paleopathology versus "curse of the pharaoh"]. / Tutanchamun: Evidenzbasierte Paleopathologie vs. "Fluch des Pharao".

AIMS: Several speculations exist regarding possible diseases of the juvenile Pharaoh Tutankhamun. In this review published paleopathological findings and artificial alterations as well as suggestions regarding underlying diseases were characterized. MATERIAL AND METHODS: A selective search of the literature was carried out in the PubMed data base in an arbitrary time interval from 1960 to 2013 (search terms: Tutankhamun, Pharaoh, paleopathology and mummy) and additional supplementary literature. RESULTS: Many artificial changes were a result of embalming and the examinations which have been performed since exhumation in 1922. Evidenced pathologies are craniofacial dysmorphia, bilateral alterations of the feet, malarial disease and an acute traumatic fracture of the knee. The cause of the knee fracture could no longer be reconstructed. Other trauma (e.g. skull fractures) or familial transmission of an eighteenth dynasty syndrome could not be confirmed. CONCLUSION: In addition to many artificial post-mortem alterations, chronic and acute diseases could be verified in Tutankhamun, although the underlying causes are partially unknown.

The course of toxicity in the pregnant mouse after exposure to the cyanobacterial toxin cylindrospermopsin: clinical effects, serum chemistries, hematology, and histopathology.

Cylindrospermopsin (CYN) is a toxin produced by a variety of fresh-water cyanobacterial species worldwide and induces significant adverse effects in both livestock and humans. This study investigated the course of CYN-induced toxicity in pregnant mice exposed daily during either the period of major organogenesis (gestation days [GD] 8-12) or fetal growth (GD13-17). Endpoints include clinical signs of toxicity, serum analyses to evaluate hepatic and renal function, histopathology of liver and kidney, and hematology. Study animals were administered 50 µg/kg CYN once daily by ip route and euthanized 24 h after 1, 2, 3, 4, or 5 consecutive doses, or 6 or 13 d after the dosing period. The course of the CYN-induced effects was determined at all euthanasia times for the endpoints just outlined. Results indicated that CYN is a toxin, producing lethality in dams during the early part of gestation, significant weight loss, and bleeding in the gastrointestinal tract, tail tip, and peri-orbital tissues. Effects also included alterations in serum markers for liver function, histopathological changes in liver and kidney tissues, electrolyte abnormalities, leukocytosis, and posttreatment thrombocytopenia and reticulocytosis. The onset of symptoms was rapid, producing reductions in weight gain in GD8-12 animals, bleeding in the vaginal area in GD13-17 animals, and significant increases in sorbitol dehydrogenase (SDH) in both groups after a single dose. Although the GD8-12 dams displayed a 50% lethality, in GD13-17 animals only a single death occurred. Alterations seen in hepatic and renal function or histopathology do not appear to be of sufficient severity to produce death. Evidence indicates that bleeding may play a critical role in the onset of symptoms and eventually, in the observed lethality.

Mode of action and dose-response framework analysis for receptor-mediated toxicity: The aryl hydrocarbon receptor as a case study.

Dioxins and dioxin-like compounds are tumor promoters that cause liver cancer in rats and mice. The aryl hydrocarbon receptor (AHR) has been implicated as a key component in this tumor promotion response. Despite extensive knowledge of the toxicology of dioxins, no mode of action (MOA) hypothesis for their tumorigenicity has been formally documented using the Human Relevance MOA framework developed by the International Programme on Chemical Safety (IPCS). To address this information gap, an expert panel was convened as part of a workshop on receptor-mediated liver tumorigenicity. Liver tumors induced by ligands of the AHR were assessed using data for dioxins and related chemicals as a case study. The panel proposed a MOA beginning with sustained AHR activation, eventually leading to liver tumors via a number of other processes, including increased cell proliferation of previously initiated altered hepatic foci, inhibition of intrafocal apoptosis and proliferation of oval cells. These processes have been identified and grouped as three key events within the hepatocarcinogenic MOA: (1) sustained AHR activation, (2) alterations in cellular growth and homeostasis and (3) pre-neoplastic tissue changes. These key events were identified through application of the Bradford-Hill considerations in terms of both their necessity for the apical event/adverse outcome and their human relevance. The panel identified data supporting the identification and dose-response behavior of key events, alteration of the dose-response by numerous modulating factors and data gaps that potentially impact the MOA. The current effort of applying the systematic frameworks for identifying key events and assessing human relevance to the AHR activation in the tumorigenicity of dioxins and related chemicals is novel at this time. The results should help direct future regulatory efforts and research activities aimed at better understanding the potential human cancer risks associated with dioxin exposure.

N,N-dimethyl-p-toluidine, a component in dental materials, causes hematologic toxic and carcinogenic responses in rodent model systems.

Because of the potential for exposure to N,N-dimethyl-p-toluidine (DMPT) in medical devices and the lack of toxicity and carcinogenicity information available in the literature, the National Toxicology Program conducted toxicity and carcinogenicity studies of DMPT in male and female F344/N rats and B6C3F1/N mice. In these studies, a treatment-related macrocytic regenerative anemia characterized by increased levels of methemoglobin and Heinz body formation developed within a few weeks of DMPT exposure in rats and mice. DMPT induced nasal cavity, splenic, and liver toxicity in rats and mice at 3 months and 2 years. DMPT carcinogenic effects were seen in the liver of male and female rats and mice, the nasal cavity of male and female rats, and the lung and forestomach of female mice. In rodents, DMPT is distributed to many of the sites where toxic and carcinogenic effects occurred. DMPT-induced oxidative damage at these target sites may be one mechanism for the treatment-related lesions. Methemoglobinemia, as seen in these DMPT studies, is caused by oxidation of the heme moiety, and this end point served as an early alert for other target organ toxicities and carcinogenic responses that followed with longer term exposure.

Similarities and differences among fluid milk products: traditionally produced, extended shelf life and ultrahigh-temperature processed.

Extended shelf life milk is a relatively new kind of fluid milk, generally manufactured by high-temperature treatment and/or micro-filtration. Being advertised as 'pasteurized milk with an extended shelf life', its flavour, compositional quality and labelling was questioned. Extended shelf life (high-temperature treatment), pasteurized ('traditionally produced') and ultrahigh-temperature milk were, therefore, compared at the beginning and end of shelf life. In triangle tests, panellists distinguished clearly between all products. High-temperature treatment milk's flavour was closer to ultrahigh-temperature and traditionally produced milk in the beginning and at the end of shelf life, respectively. Physicochemically and bacteriologically, all three types could be distinguished. Since 'extended shelf life' comprises many process varieties (each affecting flavour differently), consumer information and appropriate package labelling beyond 'long-lasting' is necessary, e.g. by mentioning the heat treatment applied.

Characterization of polybrominated diphenyl ether toxicity in Wistar Han rats and use of liver microarray data for predicting disease susceptibilities.

The toxicity of polybrominated diphenyl ethers (PBDEs), flame-retardant components, was characterized in offspring from Wistar Han dams exposed by gavage to a PBDE mixture (DE71) starting at gestation day 6 and continuing to weaning on postnatal day (PND) 21. Offspring from the dams underwent PBDE direct dosing by gavage at the same dose as their dams from PND 12 to PND 21, and then after weaning for another thirteen weeks. Liver samples were collected at PND 22 and week 13 for liver gene expression analysis (Affymetrix Rat Genome 230 2.0 Array). Treatment with PBDE induced 1,066 liver gene transcript changes in females and 1,200 transcriptional changes in males at PND 22 (false discovery rate < 0.01), but only 263 liver transcriptional changes at thirteen weeks in male rats (false discovery rate < 0.05). No significant differences in dose response were found between male and female pups. Transcript changes at PND 22 coded for proteins in xenobiotic, sterol, and lipid metabolism, and cell cycle regulation, and overlapped rodent liver transcript patterns after a high-fat diet or phenobarbital exposure. These findings, along with the observed PBDE-induced liver hypertrophy and vacuolization, suggest that long-term PBDE exposure has the potential to modify cell functions that contribute to metabolic disease and/or cancer susceptibilities.

Process control in cell culture technology using dielectric spectroscopy.

In the biopharmaceutical industry, mammalian and insect cells as well as plant cell cultures are gaining worldwide importance to produce biopharmaceuticals and as products themselves, for example in stem cell therapy. These highly sophisticated cell-based production processes need to be monitored and controlled to guarantee product quality and to satisfy GMP requirements. With the process analytical technology (PAT) initiative, requirements regarding process monitoring and control have changed and real-time in-line monitoring tools are now recommended. Dielectric spectroscopy (DS) can serve as a tool to satisfy some PAT requirements. DS has been used in the medical field for quite some time and it may allow real-time process monitoring of biological cell culture parameters. DS has the potential to enable process optimization, automation, cost reduction, and a more consistent product quality. Dielectric spectroscopy is reviewed here as a tool to monitor biochemical processes. Commercially available dielectric sensing systems are discussed. The potential of this technology is demonstrated through examples of current and potential future applications in research and industry for mammalian and insect cell culture.

[Retinal photoablation with the Erbium:YAG laser. Initial experimental results for traction-free removal of tissue]. / Retinale Photoablation mit dem Erbium:YAG-Laser. Erste experimentelle Ergebnisse zur traktionsfreien Gewebeabtragung.

BACKGROUND: To investigate the potential of an Er:YAG laser for precise and traction-free removal of retinal layers in vitro. MATERIAL AND METHODS: Retinal ablation in porcine retinal explants was performed using a free running Er:YAG laser focused either into a low-OH quartz fiber or a sapphire fiber. The explants were treated under air or perfluorodecaline (PFD). The ablation depth was evaluated by optical coherence tomography (OCT) and histology sections. RESULTS: A radiant exposure of 5.0 J/cm(2) under air and PFD resulted in complete transsection of the neurosensory retina. Between 3.5 and 2.0 J/cm(2) the ablation depth and the defect patterns varied markedly and adjacent thermal zones areas were seen. Below 2.0 J/cm(2) no defects could be created in air, whereas under PFD the ablation extended into the ganglion cell layer. Ablations using a sapphire fiber and 2.0 J/cm(2) showed a significantly higher reproducibility of ablation depth, and homogeneous defect patterns limited to the nerve fiber layer could be produced without thermal damage. CONCLUSIONS: The Er:YAG laser system with a low-OH quartz fiber allowed ablation of inner retinal layers in vitro, but revealed a variable ablation depth and low reproducibility.However, a sapphire fiber showed markedly improved results. Therefore its use during vitreoretinal surgery seems possible not only as a cutting device but also as a tool for the ablation of fine retinal structures.

Testing local independence between two point processes.

Dependencies between two types of points in a spatial point process can be due either to a real dependence between the two types or to the dependence on common underlying variables. We propose a global test for dependence between two point processes that is valid for a wide range of models. In contrast with previously proposed methods, it is based on a number of local test statistics, which makes it possible to map the local association between the two processes. The behavior of the test is evaluated by a simulation study. It is then applied to a vegetation pattern data set from Burkina Faso.

Testing local dependence of spatial structures on images

Associations between two spatial processes can be due to a real dependence between the two processes or to the dependence on common underlying variables. We propose to test the existence of a real dependence by use of local tests, leading to a global test of real dependence and a map of local interactions. We present first how classical interaction tests based on random rotations between completely observed processes such as those developed by Berman (Berman. Appl. Statist. (1986) 35, 54-62), can be integrated in local analyses. For this purpose, tests are first performed locally, and the distribution of their p-values is then compared to the corresponding value under the null hypothesis. A similar approach is proposed to test non-stationarity of a point pattern by using distance statistics popularized by Diggle (Diggle. Statistical Analysis of Spatial Point Patterns. (1983) Academic Press, New York). The problem of testing the interaction between a random field and a censoring area pattern process is discussed and an approach similar to the preceding ones is then proposed. The methods are mainly applied to agricultural examples but they can be applied to any microscopical images for which one wishes to analyse the spatial structure.

[Long-term effect of inhaled budesonide in patients with mild to moderate chronic obstructive lung disease. The Osterbro Study]. / Langtidsvirkningen af inhaleret budesonid hos patienter med mild og moderat kronisk obstruktiv lungesygdom. Osterbro lunge studie.

We compared the effect of inhaled budesonide with placebo on decline in lung function and respiratory symptoms in a three-year study of patients with chronic obstructive pulmonary disease (COPD). We used a parallel-group, randomized, double-blind, placebo-controlled design, nested in an ongoing epidemiological survey. Patients were non-asthmatic subjects with a decreased ratio between forced expiratory volume in one second (FEV1) and vital capacity (VC); i.e., FEV1/VC < or = 0.7. All included patients had an FEV1 which was irreversible to both inhaled terbutaline and prednisolone. Two hundred and ninety patients were randomized to receive either budesonide, 1200 mcg. daily for six months followed by 800 mcg. daily for 30 months, or placebo for 36 months. Patients had a mean age of 59 years and their mean FEV1 was 2.37 liters or 86% of predicted. Crude FEV1 declines were 41.8 ml/year in the placebo group and 45.1 ml/year in the budesonide group. Using a regression model in the intention-to-treat population, patients in the placebo group had an FEV1 decline of 49.1 ml/year in contrast to 46.0 ml/year in the budesonide group; the estimated difference 3.1 ml/year (95% confidence interval--12.8-19.0) was statistically insignificant, p = 0.70. No effect of inhaled budesonide was seen on respiratory symptoms or number of exacerbations. These findings question the role of longterm inhaled corticosteroids in the treatment of mild-moderate COPD.

Long-term effect of inhaled budesonide in mild and moderate chronic obstructive pulmonary disease: a randomised controlled trial.

BACKGROUND: Little is known about the long-term efficacy of inhaled corticosteroids in chronic obstructive pulmonary disease (COPD). We investigated the efficacy of inhaled budesonide on decline in lung function and respiratory symptoms in a 3-year placebo-controlled study of patients with COPD. METHODS: We used a parallel-group, randomised, double-blind, placebo-controlled design in a singlecentre study, nested in a continuing epidemiological survey (the Copenhagen City Heart Study). Inclusion criteria were as follows: no asthma; a ratio of forced expiratory volume in 1 s (FEV1) and vital capacity of 0.7 or less; FEV1 which showed no response (<15% change) to 1 mg inhaled terbutaline or prednisolone 37.5 mg orally once daily for 10 days. 290 patients were randomly assigned budesonide, 800 microg plus 400 microg daily for 6 months followed by 400 microg twice daily for 30 months, or placebo for 36 months. The mean age of the participants was 59 years and the mean FEV1 2.37 L or 86% of predicted. The main outcome measure was rate of FEV1 decline. Analyses were by intention to treat. FINDINGS: The crude rates of FEV1 decline were slightly smaller than expected (placebo group 41.8 mL per year, budesonide group 45.1 mL per year). The estimated rates of decline from the regression model did not differ significantly (49.1 mL vs 46.0 mL per year; difference 3.1 mL per year [95% CI -12.8 to 19.0]; p=0.7). Before the study, the minimum relevant difference was defined as 20 mL per year; this difference was outside the 95% CI. No effect of inhaled budesonide was seen on respiratory symptoms. 316 exacerbations occurred during the study period, 155 in the budesonide group and 161 in the placebo group. Treatment was well tolerated. INTERPRETATION: Inhaled budesonide was of no clinical benefit in COPD patients recruited from the general population by screening. We question the role of long-term inhaled corticosteroids in the treatment of mild to moderate COPD.

Extreme, progressive isovolemic hemodilution with 5% human albumin, PentaLyte, or Hextend does not cause hepatic ischemia or histologic injury in rabbits.

BACKGROUND: Physicians and their patients are greatly concerned about perioperative blood administration. Although isovolemic hemodilution is utilized to decrease the incidence of transfusion, it is unclear at what degree of hemodilution hepatoenteric ischemia and injury occurs. The authors hypothesized that hepatic ischemia, systemic ischemia, and tissue injury would occur during hemodilution in rabbits, and that the severity of ischemia and injury may be dependent on the fluid administered. METHODS: Rabbits anesthetized with isoflurane were assigned randomly to a sham-operated group (n = 8) or groups that underwent four isovolemic hemodilutions (25% of the blood volume removed at hourly intervals), with blood replaced with one of three solutions: balanced electrolyte solutions containing 6% pentastarch (n = 8), 6% hetastarch (n = 9), or 5% human albumin in normal saline (n = 8). Arterial ketone body ratio and plasma lactate, respectively, served as measures of hepatic and systemic ischemia. Gastric, duodenal, and hepatic histologic injury was assessed post mortem. RESULTS: Hemodilution from a baseline hematocrit of about 33% to about 8% (third hemodilution) with all three colloids did not result in a significant increase in plasma lactate concentration or decrease in arterial ketone body ratio. At a hematocrit of about 5% (fourth hemodilution), the hetastarch group had a significantly (P < 0.05) greater plasma lactate concentration than the sham-operated and 5% human albumin groups. There were no significant differences in arterial ketone body ratio or histologic injury between the groups. CONCLUSIONS: Isovolemic hemodilution (approximately 5% hematocrit) with albumin, pentastarch, or hetastarch solutions does not result in significant hepatic ischemia or injury assessed by histology.

The safety of OP-1 for lumbar fusion with decompression-- a canine study.

OBJECTIVE: Bone morphogenetic proteins can serve as adjuncts to autologous bone to achieve bony fusion, and recombinant BMPs such as osteogenic protein-1 (OP-1) have the potential to replace autologous bone altogether as fusion substrate. However, relatively little is known about the safety of OP-1 for spinal fusion procedures. This study examined the effects of OP-1 intentionally placed in the subarachnoid space following thecal sac decompression, and used as graft substrate in a canine dorsolateral lumbar spine fusion model. METHODS: Lumbar decompression with dorsolateral fusion was performed on 30 canines. The dura was opened to simulate an intraoperative rent and OP-1 was placed in the subarachnoid space and in the fusion bed. Animals were sacrificed after 16 weeks and the spines were examined manually, radiographically and pathologically. RESULTS: All animals treated with OP-1 developed new bone in the subarachnoid space. This bone compressed the spinal cord, but no clinical or pathological features of neurotoxicity were noted. Mild spinal stenosis was noted at the site of dural decompression in the OP-1 treated animals. Over 80% of animals treated with OP-1 developed fusion as assessed by palpation (52% by CT criteria), while only 25% of control animals fused. CONCLUSIONS: Recombinant human OP-1 is effective at promoting fusion in a canine dorsolateral lumbar spine fusion model. However, bone growth can occur over exposed, decompressed dura, and it can form in the subdural and subarachnoid spaces. The use of OP-1 as an adjunct to spinal fusion appears to have merit, but its use must be carefully controlled to avoid unwanted bone formation and subsequent neural compression.

Targeted disruption of mouse long-chain acyl-CoA dehydrogenase gene reveals crucial roles for fatty acid oxidation.

Abnormalities of fatty acid metabolism are recognized to play a significant role in human disease, but the mechanisms remain poorly understood. Long-chain acyl-CoA dehydrogenase (LCAD) catalyzes the initial step in mitochondrial fatty acid oxidation (FAO). We produced a mouse model of LCAD deficiency with severely impaired FAO. Matings between LCAD +/- mice yielded an abnormally low number of LCAD +/- and -/- offspring, indicating frequent gestational loss. LCAD -/- mice that reached birth appeared normal, but had severely reduced fasting tolerance with hepatic and cardiac lipidosis, hypoglycemia, elevated serum free fatty acids, and nonketotic dicarboxylic aciduria. Approximately 10% of adult LCAD -/- males developed cardiomyopathy, and sudden death was observed in 4 of 75 LCAD -/- mice. These results demonstrate the crucial roles of mitochondrial FAO and LCAD in vivo.

PentaLyte decreases lung injury after aortic occlusion-reperfusion.

Lung injury often occurs after hepatoenteric ischemia, with xanthine oxidase (XO, an oxidant-generating enzyme), released from reperfusing liver and intestines, mediating a significant component of this injury. Since pentastarch administration decreases intestinal reperfusion injury, we determined whether resuscitation with PentaLyte (a pentastarch-containing solution) would decrease hepatoenteric reperfusion injury, xanthine oxidase release, and concomitant lung injury after aortic occlusion- reperfusion. Aortic occlusion was established in rabbits for 40 min, and was followed by 3 h of reperfusion, during which either PentaLyte or lactated Ringer's solution-based resuscitation was administered. Sham-operated animals served as controls. Hepatoenteric reperfusion injury, as manifested by release of the enzyme aspartate aminotransferase and decreased gastric intramucosal pH, was significantly (p < 0.0167) attenuated by PentaLyte administration after aortic occlusion-reperfusion, as compared with its occurrence in animals given lactated Ringer's solution. The release of XO after aortic occlusion-reperfusion was 4-fold smaller after PentaLyte administration than after resuscitation with lactated Ringer's solution (p < 0.05). Pulmonary injury, as defined by an increase in bronchoalveolar lavage fluid (BALF) protein content and lactate dehydrogenase (LDH) activity, was 4-fold less after PentaLyte administration following aortic occlusion-reperfusion than after administration of lactated Ringer's solution (p < 0.05). We conclude that remote pulmonary injury is significantly decreased by concomitant PentaLyte-mediated reduction of hepatoenteric reperfusion injury and XO release.

Functional correction of short-chain acyl-CoA dehydrogenase deficiency in transgenic mice: implications for gene therapy of human mitochondrial enzyme deficiencies.

We report the therapeutic effects of liver-specific expression of a short-chain acyl-CoA dehydrogenase (SCAD) transgene in the SCAD-deficient mouse model. Transgenic mice were produced with a rat albumin promoter/enhancer driving a mouse SCAD minigene (ALB-SCAD) on both the SCAD normal genetic background and a SCAD-deficient background. In three transgenic lines produced on the SCAD-deficient background, recombinant SCAD activity and antigen in liver mitochondria were found up to 7-fold of normal control values. All three lines showed a markedly reduced organic aciduria and fatty liver, which are sensitive indicators of the metabolic abnormality seen in this disease found in children. We found no detrimental effects of high liver SCAD expression in transgenic mice on either background. These studies provide important basic and practical therapeutic information for the potential gene therapy of nuclear-encoded mitochondrial enzyme deficiencies, as well as insights into the mechanisms of the disease.

Hextend (hetastarch solution) decreases multiple organ injury and xanthine oxidase release after hepatoenteric ischemia-reperfusion in rabbits.

OBJECTIVE: We hypothesized that multiple organ injury and concentrations of xanthine oxidase (an oxidant-generating enzyme released after hepatoenteric ischemia) would be decreased by the administration of a bolus of a colloid solution at reperfusion. DESIGN: Randomized, masked, controlled animal study. SETTING: University-based animal research facility. SUBJECTS: Fifty-four New Zealand white male rabbits, weighing 2 to 3 kg. INTERVENTIONS: Anesthetized rabbits were assigned to either the hepatoenteric ischemia-reperfusion group (n = 27) or the sham-operated group (n = 27). Hepatoenteric ischemia was maintained for 40 mins with a balloon catheter in the thoracic aorta, followed by 3 hrs of reperfusion. Each group was randomly administered a bolus of one of three fluids at the beginning of reperfusion: Hextend (hetastarch solution); 5% human albumin; or lactated Ringer's solution. The investigators were masked as to the identity of the fluid administered. MEASUREMENTS AND MAIN RESULTS: Multiple organ injury was assessed by the release of lactate dehydrogenase activity into the plasma and by indices of gastric and pulmonary injury. Circulating lactate dehydrogenase activity was significantly greater (p < .001) in animals receiving lactated Ringer's solution than in rabbits receiving either colloid solution. Gastric injury (tissue edema, Histologic injury Score) was significantly decreased (p < .01) by administration of both colloid solutions. Lung injury (bronchoalveolar lavage lactate dehydrogenase activity) was significantly decreased (p < .05) by the hetastarch solution administration. The hetastarch solution administration resulted in 50% less xanthine oxidase activity release during reperfusion compared with albumin or lactated Ringer's solution administration (p < .001). CONCLUSION: We conclude that multiple organ injury and xanthine oxidase release after hepatoenteric ischemia-reperfusion are decreased by colloid administration.