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PubMed2005

The design of multicentre trials.

The analysis of data collected in multicentre trials offers challenges because the data from the individual centres must be combined in some way to give an overall evaluation of the differences between the treatments in the trial. We propose that the combined response to treatment (CRT) be used as this overall measure. The definition and estimation of the CRT can be derived from either a fixed-effects or a random-effects model. For the latter we introduce the ECRT--the expected combined response to treatment. We describe and compare both types of model and express our preference for the random-effects model. We stress that the number of patients enrolled at a centre is a random variable and show that this source of randomness inflates the variance of the estimated ECRT. Variability in enrolment rates over the centres further inflates this variance. A simple conclusion from our results is that if variability in the treatment and centre effects, in the enrolment time, in the number of patients enrolled at a centre and in the enrolment rates is not properly accounted for, then an underpowered trial may result. Using properties of estimators generated by the random-effects model we propose methods for determining the optimal number of centres and total number of patients to enrol in a trial to minimize a loss function that accounts for centre and patient costs and loss of revenue. We discuss variants of the loss function and corresponding optimization problems for different types of enrolment. We end the paper with brief generalizations of the developed techniques to the case where the response is binary.

Depression↗

PubMed1998

The collaborative UK ECMO (Extracorporeal Membrane Oxygenation) trial: follow-up to 1 year of age.

OBJECTIVE: To evaluate the clinical effectiveness of neonatal extracorporeal membrane oxygenation (ECMO), in terms of mortality and morbidity, in the treatment of cardiorespiratory failure in term infants. METHODS: The criteria for trial entry were: an oxygenation index of >40 or arterial partial pressure of carbon dioxide (PaCO2) >12 kPa for at least 3 hours; gestational age at birth of 35 completed weeks or more; a birth weight of 2 kg or more; <10 days high-pressure ventilation; an age of <28 days; and no contraindication to ECMO such as previous cardiac arrest or intraventricular hemorrhage. Eligible infants were randomized either to be transferred to one of five ECMO centers in the United Kingdom or to continue conventional treatment. The principal outcome was death or severe disability at the age of 1 year. Severe disability was defined as an overall developmental quotient of <50 using the Griffiths Mental Development Scales, or blindness or a level of function so as to make assessment using the Griffiths Scales impossible. Families of surviving children were contacted at regular intervals during the first year and at the age of 1, and an assessment of the child was performed by one of three developmental pediatricians. This included a neurologic examination, assessment of hearing and vision, developmental level, general health, and health service use. RESULTS: Of 185 infants recruited into the trial, 93 infants were in the ECMO arm and 92 were allocated conventional treatment. The groups were comparable at trial entry. Thirty of 93 (32%) ECMO infants died before the age of 1 year and 54 of 92 (59%) of the infants in the conventional group died. Two infants were lost to follow-up, 1 from each arm of the trial. Of the remaining 99 survivors, at the age of 1 year, 2 infants (1 in each arm) were still in the hospital, and 5 (3 in the ECMO arm and 2 conventional) still required supplementary oxygen. Fifteen infants had tone changes in the limbs, 10/62 (16%) in the ECMO arm and 5/37 (13.5%) in the conventional arm. These signs were more common on the left side in both groups. One infant (in the ECMO arm) had bilateral sensorineural deafness and 1 infant (also in the ECMO arm) had low vision. Overall, 2 infants were severely disabled (1 ECMO and 1 conventional), 16 others also had evidence of functional loss (12 vs 4), and 8 had impairment without functional loss (4 vs 5). There was a trend toward proportionately greater respiratory morbidity in the conventional group. Neurologic morbidity was more common in the ECMO group, reflecting the larger number of survivors. The lower rate of adverse primary outcome (death or severe disability at 1 year) was found among infants allocated ECMO in all the predefined stratified analyses. Disease severity at trial entry and type of referral center did not appear to alter the effects of ECMO. Only 4 of 18 infants with congenital diaphragmatic hernia survived and at age 1 year only 1 of the 4 survivors was considered normal. CONCLUSION: These results are in accord with the earlier preliminary findings that a policy of ECMO support reduces the risk of death without a concomitant rise in severe disability. However, 1 in 4 survivors had evidence of impairment with or without disability. Further follow-up is planned at the age of 4 and 7 years.

Developmental Disabilities↗

PubMed1991

Reciprocal apparatus dysfunction as a cause of severe hind limb lameness in a horse.

A 2-year-old Appaloosa mare was admitted because of acute, severe hind limb lameness (grade 4 of 5). The hock could be flexed or extended without influencing the position of the stifle joint, and the fetlock and proximal interphalangeal joints could be extended while the hock was maintained in flexion. The diagnosis was functional loss of the reciprocal apparatus. The differential diagnoses for functional loss of the reciprocal apparatus include disruption of the common calcaneal tendon, the gastrocnemius muscle, the peroneus tertius, or the superficial digital flexor muscle. In this horse, the diagnosis was disruption of the superficial digital flexor muscle. The horse made an excellent recovery following 5 months of stall confinement.

Acute Disease↗

PubMed1992

Simultaneous gain and loss of functions caused by a single amino acid substitution in the beta subunit of Escherichia coli RNA polymerase: suppression of nusA and rho mutations and conditional lethality.

Transcript elongation and termination in Escherichia coli is modulated, in part, by the nusA gene product, an acidic protein that interacts not only with RNA polymerase itself but also with ancillary factors, namely the host termination protein Rho and phage lambda antitermination protein, N. The E. coli nusA1 mutant fails to support lambda development due to a specific defect in N-mediated antitermination. Certain rifampicin-resistant (rifR) variants of the nusA1 host support lambda growth. We report here the isolation and pleiotropic properties of one such rifR mutant, ts8, resulting from a single amino acid substitution mutation in rpoB, the structural gene for polymerase beta subunit. ts8 is a recessive lethal mutation that blocks cell growth at 42 degrees. Pulse-labeling and analysis of newly synthesized proteins indicate that the mutant cell is proficient in RNA synthesis at high temperature. Apparently, ts8 causes a loss of some specialized function of RNA polymerase without a gross defect in general transcription activities. ts8 is an allele-specific suppressor of nusA1. It does not suppress nusAsal, nusB5 and nusE71 mutations nor does it bypass the requirement for a functional N gene and the nut site for antitermination and lambda growth. A mutation in the N gene, punA1, that restores lambda growth in the nusA1 mutant host but not in the nusAsal host, compensates for the nusAsal allele in the ts8 mutant. This combined effect of two allele-specific suppressors suggests that they enhance some aspect of polymerase-NusA-N interaction and function. ts8 suppresses the rho15 mutation, but not the rho112 mutation, indicating that it might render RNA polymerase susceptible to the action of a defective Rho protein. Marker rescue analysis has localized ts8 to a 910-bp internal segment of rpoB that encodes the Rif domain. By amplification, cloning and sequencing of this segment of the mutant chromosome we have determined that ts8 contains Phe in place of Ser522, caused by a C to T transition. By gene conversion, we have established that the simultaneous gain and loss of three functions of polymerase is caused by this single amino acid substitution. Clearly, a site in the beta subunit critical for the functioning of both termination and antitermination factors is altered by ts8. The alteration, we imagine, might make this site on polymerase receptive to some factors but repulsive to others.

Alleles↗

PubMed1998

Moderate loss of function of cyclic-AMP-modulated KCNQ2/KCNQ3 K+ channels causes epilepsy.

Epilepsy affects more than 0.5% of the world's population and has a large genetic component. It is due to an electrical hyperexcitability in the central nervous system. Potassium channels are important regulators of electrical signalling, and benign familial neonatal convulsions (BFNC), an autosomal dominant epilepsy of infancy, is caused by mutations in the KCNQ2 or the KCNQ3 potassium channel genes. Here we show that KCNQ2 and KCNQ3 are distributed broadly in brain with expression patterns that largely overlap. Expression in Xenopus oocytes indicates the formation of heteromeric KCNQ2/KCNQ3 potassium channels with currents that are at least tenfold larger than those of the respective homomeric channels. KCNQ2/KCNQ3 currents can be increased by intracellular cyclic AMP, an effect that depends on an intact phosphorylation site in the KCNQ2 amino terminus. KCNQ2 and KCNQ3 mutations identified in BFNC pedigrees compromised the function of the respective subunits, but exerted no dominant-negative effect on KCNQ2/KCNQ3 heteromeric channels. We predict that a 25% loss of heteromeric KCNQ2/KCNQ3-channel function is sufficient to cause the electrical hyperexcitability in BFNC. Drugs raising intracellular cAMP may prove beneficial in this form of epilepsy.

Amino Acid Sequence↗

PubMed1988

Tumorous-head-type mutants of the distal bithorax complex cause dominant gain and recessive loss of function in Drosophila melanogaster.

The homeotic mutants tuh-3, SGA62, I127, and R17.32 are located in the abdominal portion of the bithorax complex in Drosophila melanogaster. The genes act as semidominants in the head, causing a gain of expression of leg, genitalia, tergite, or combinations of the structures. SGA62, tuh-3, and I127 additionally act as recessives in the posterior abdomen, causing a loss of these functions. Each mutant has its own focus of expression in the head region. I127 and tuh-3 can cause head defects only in the presence of the recessive maternal effect allele tuh-1h, while SGA62 and R17.32 cause head defects in the absence of this maternal effect. In the presence of the dominant tuh-1g maternal effect allele, the tuh-3 and I127 heads are normal. However, these flies now show a genital disc defect. SGA62 homozygotes have abdominal segments 6 and 7 transformed into a more anterior segment irrespective of the maternal effect in force. R17.32 appears to map to the abd-A domain, while SGA62, I127, and tuh-3 belong to Abd-B. SGA62 is located in the morphogenetic element of Abd-B, while I127 has characteristics of mutants affecting both the morphogenetic and regulatory elements of Abd-B. The tuh-3 mutant is within the regulatory element. The maternal effect alleles appear to interact specifically with mutants in the regulatory region of Abd-B.

Alleles↗

PubMed2005

Pervasive loss of function in asylum-seeking children in Sweden.

UNLABELLED: Presently, a couple of hundred children from traumatized asylum-seeking families in Sweden have developed severe loss of mental and physical functions without evidence of underlying disease. Of the 23 treated children treated at this clinic, 15 have recovered, three are improving and five are under initial care. Communication within the family is crucial from both pathogenic and salutogenic perspectives. A permanent residence permit, correcting the underlying situation of threat and insecurity, is a condition for good results from psychiatric treatment. In Sweden there is a lack of consensus and conflicting political and medical perspectives prevail regarding the "apathetic" children. CONCLUSION: Children living under unbearable life conditions can develop life-threatening depression-withdrawal stress reactions well known as pervasive refusal syndrome (PRS). This is also true of children in traumatized asylum-seeking families. Excellent results are achieved when the family's underlying fear and hopelessness can be erased and the treatment focuses on the traumatic experiences.

Child↗

PubMed1996

Loss of function of cytochrome c in Jurkat cells undergoing fas-mediated apoptosis.

Mitochondrial function was examined in Jurkat cells undergoing Fas-mediated apoptosis. With succinate or ascorbate/tetramethylphenylenediamine as substrate, oxygen uptake by digitonin-permeabilized apoptotic mitochondria was greatly decreased as compared with control. Assessment of the function of the cytochrome c-cytochrome oxidase segment of the electron transport chain of apoptotic mitochondria showed that the activity of cytochrome oxidase appeared to be normal, but that of cytochrome c was greatly diminished. A death protease was found to participate in the events leading to the loss of cytochrome c activity, but the cytochrome did not seem to be extensively degraded during the course of apoptosis. Our results suggest that a rapid loss in mitochondrial function due at least in part to the inhibition or inactivation of cytochrome c is a potentially fatal component of the apoptosis program of Jurkat cells.

Apoptosis↗

PubMed1999

Achromatic and short-wavelength automated perimetry in patients with glaucomatous large cups.

OBJECTIVE: To evaluate visual function and optic disc features in patients with large cup-disc ratios (C/Ds). METHODS: One eye of 86 patients with vertical C/Ds by contour of at least 0.8, who had undergone both standard achromatic automated perimetry (SAP) and short-wavelength automated perimetry (SWAP) testing, was selected retrospectively. Two masked glaucoma specialists independently graded stereoscopic photographs for vertical C/Ds, rim thinning, notching, excavation, optic disc hemorrhages, and nerve fiber layer defects. Visual fields were classified as abnormal if the glaucoma hemifield test result, corrected pattern standard deviation, or mean deviation was outside age-specific normal limits. Confocal scanning laser ophthalmoscopy was used to determine disc area. RESULTS: SAP and SWAP results were abnormal in 44 (51%) and 52 (60%) of 86 patients, respectively. In patients with normal SAP results, SWAP results were abnormal in 14 (33%) of 42 patients. In patients with normal SWAP results, SAP results were abnormal in 6 (18%) of 34 patients. Small discs are associated with an abnormal SAP result (P = .01) and an abnormal SWAP result (P = .09). An increased vertical C/D greater than the qualifying level of 0.8 was associated with an abnormal SAP or SWAP result (P< or =.001). Rim thinning (P = .01) and disc hemorrhages (P = .04) were associated with an abnormal SAP result. CONCLUSIONS: Many patients with large C/Ds have normal SAP and SWAP results. Compared with SAP, SWAP results were abnormal in a higher percentage of these patients. If a patient has a large C/D and normal SAP results, SWAP testing may detect functional loss earlier. If glaucoma is defined by both structural and functional loss, patients with large vertical C/Ds, normal SAP results, and abnormal SWAP results may have glaucoma. Longitudinal studies are needed to assess this hypothesis and determine whether these patients subsequently develop abnormal SAP results as well.

Adult↗

PubMed2002

Predictive value of short-wavelength automated perimetry: a 3-year follow-up study.

PURPOSE: To determine whether structural changes in the retinal nerve fiber layer (RNFL) and functional abnormalities in short-wavelength automated perimetry (SWAP) can predict the onset of functional losses in standard automated perimetry patients suspected of having glaucoma. DESIGN: Prospective observational case series. PARTICIPANTS: A total of 160 eyes of ocular hypertensive subjects (intraocular pressure greater than 21 mmHg and normal standard automated perimetry) were included in the study. INTERVENTIONS: The subjects underwent RNFL photographic evaluation and SWAP. Standard automated perimetries were repeated after 3 years to evaluate glaucomatous losses. MAIN OUTCOME MEASURES: Onset of glaucomatous defects in conventional automated perimetry after 3 years of follow-up, with or without prior glaucomatous defects in RNFL and SWAP. RESULTS: At the beginning of the study, 77 eyes showed RNFL losses (48%), and 58 eyes showed abnormalities in SWAP (36%). After the 3-year follow-up period, 14 of 77 eyes with RNFL losses had standard automated perimetry abnormalities (predicting sensitivity 93%), whereas 11 of 58 eyes with abnormal SWAP had standard automated perimetry losses (73% sensitivity). CONCLUSIONS: RNFL and SWAP losses are signs of early glaucomatous damage and can predict functional losses in standard automated perimetry.

Adult↗

PubMed2005

High morning home blood pressure is associated with a loss of functional independence in the community-dwelling elderly aged 75 years or older.

To elucidate the relationship between home systolic blood pressure (SBP) and functional impairment in the elderly 75 years or older, 461 community-dwelling subjects (192 men, 269 women, mean age: 80 years) were studied. Home blood pressure was measured twice in the morning and twice in the evening for 5 consecutive days with an automatic cuff-oscillometric device. Total/high-density lipoprotein cholesterol and several functional assessments were evaluated. A subject was determined to exhibit a loss of independence according to the activities of daily living (ADL) score in a study conducted in 2001. Based on the mean home SBPs (mSBP) and morning-evening SBP differences (dSBP), the subjects were classified into 4 groups as follows: hypertensive/morning-dominant (HM; mSBP > or = 135 mmHg, dSBP > or = 15 mmHg), hypertensive/sustained (HS; mSBP > or = 135 mmHg, dSBP<15 mmHg), normotensive/morning-dominant (NM; mSBP<135 mmHg, dSBP > or = 15 mmHg), and normotensive/controlled (NC; mSBP<135 mmHg, dSBP<15 mmHg). There were no differences in sex, cholesterol levels, history of stroke, other cardiovascular diseases (CVDs), and cognitive function, but there were significant differences in age, antihypertensive medications, the neurobehavioral test scores, and ADL scores. There were no significant differences in terms of mortality and CVD events. In the survivors, HM and HS were independent risk factors for a loss of independence, after adjustments were made for onset of stroke, age, antihypertensive therapy, history of CVD, as well as neurobehavioral test scores and ADL scores (odds ratio [OR]: 12.2 and 3.78, respectively). After the same adjustments as those mentioned above were made, HM and HS were found to be negative determinants of survival and maintenance of independence (OR: 0.082, 0.270, respectively). In conclusion, high home SBP (> or = 135 mmHg) and high dSBP (> or = 15 mmHg) were found to be important in determining the levels of disability for the very elderly.

Activities of Daily Living↗

PubMed1994

Dose-dependent reduction of tissue loss and functional impairment after spinal cord trauma with the AMPA/kainate antagonist NBQX.

Initial studies on the role of glutamate receptors in traumatic spinal cord injury (SCI) implicated the NMDA subclass of ionotropic glutamate receptors in contributing to functional deficits. Recently we obtained evidence suggesting that non-NMDA ionotropic receptors may participate in producing a portion of the behavioral impairment after SCI. To test this hypothesis we have conducted a dose-response experiment, focally injecting 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(f)quinoxaline (NBQX; 1.5, 5, or 15 nmol), a highly selective antagonist of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)/kainate receptors, or vehicle alone, into the injury site beginning at 15 min after a standardized contusive SCI. Behavioral tests of hindlimb reflex and coordinated sensorimotor function were performed 1 d after injury and weekly thereafter. At 4 weeks, spinal cord tissue was examined using quantitative histopathological and immunocytochemical techniques. We found a dose-dependent reduction in tissue loss at the thoracic injury site, with greater residual amounts of both gray matter and myelinated white matter. The maximum dose (15 nmol) significantly reduced the average length of the lesions and doubled the area of residual white matter at the epicenter. Serotonin immunoreactivity caudal to the lesion, used as a marker for descending motor control axons, was also increased in a dose-related manner and nearly tripled with the highest dose of NBQX as compared to controls. Most importantly, the reduced tissue loss in NBQX-treated groups was correlated with reduced functional deficits. There was a dose-dependent enhancement of speed and degree of recovery of both reflex and coordinated hindlimb motor activity, and reduction in the time required for establishing a reflex bladder. The long-term functional deficits at 4 weeks after SCI were reduced in a dose-related manner. Further, regression analyses demonstrated a significant correlation between the increase in amount of residual tissue and improvement in hindlimb function. Our results suggest that in this type of incomplete contusive SCI, a large and functionally important proportion of the tissue loss appears to be due to secondary injury mediated by local AMPA/kainate receptors.

Animals↗

PubMed2006

T118M PMP22 mutation causes partial loss of function and HNPP-like neuropathy.

OBJECTIVE: To determine the clinical consequences of the PMP22 point mutation, T118M, which has been previously considered to either cause an autosomal recessive form of Charcot-Marie-Tooth (CMT) disease or be a benign polymorphism. METHODS: We analyzed patients from five separate kindreds and characterized their peripheral nerve function by clinical and electrophysiological methods. RESULTS: All heterozygous patients had clinical and/or electrophysiological features of a neuropathy similar to hereditary neuropathy with liability to pressure palsies (HNPPs). The homozygous patient had a severe axonal neuropathy without features of demyelination. INTERPRETATION: These findings suggest that T118M PMP22 retains some normal PMP22 activity, allowing the formation of compact myelin and normal nerve conduction velocities in the homozygous state. Taken together, these findings suggest that T118M is a pathogenic mutation causing a dominantly inherited form of CMT by a partial loss of PMP22 function.

Adult↗

PubMed2006

Hybrid approach of selecting hyperparameters of support vector machine for regression.

To select the hyperparameters of the support vector machine for regression (SVR), a hybrid approach is proposed to determine the kernel parameter of the Gaussian kernel function and the epsilon value of Vapnik's epsilon-insensitive loss function. The proposed hybrid approach includes a competitive agglomeration (CA) clustering algorithm and a repeated SVR (RSVR) approach. Since the CA clustering algorithm is used to find the nearly "optimal" number of clusters and the centers of clusters in the clustering process, the CA clustering algorithm is applied to select the Gaussian kernel parameter. Additionally, an RSVR approach that relies on the standard deviation of a training error is proposed to obtain an epsilon in the loss function. Finally, two functions, one real data set (i.e., a time series of quarterly unemployment rate for West Germany) and an identification of nonlinear plant are used to verify the usefulness of the hybrid approach.

Algorithms↗

PubMed2003

Mutations of SPG4 are responsible for a loss of function of spastin, an abundant neuronal protein localized in the nucleus.

Mutations of spastin are responsible for the most common autosomal dominant form of hereditary spastic paraplegia (AD-HSP), a disease characterized by axonal degeneration of corticospinal tracts and posterior columns. Generation of polyclonal antibodies specific to spastin has revealed two isoforms of 75 and 80 kDa in both human and mouse tissues with a tissue-specific variability of the isoform ratio. Spastin is an abundant protein in neural tissues and immunolabeling experiments have shown that spastin is expressed in neurons but not in glial cells. These data indicate that axonal degeneration linked to spastin mutations is caused by a primary defect of neurons. Protein and transcript analyses of patients carrying either nonsense or frameshift spastin mutations revealed neither truncated protein nor mutated transcripts, providing evidence that these mutations are responsible for a loss of spastin function. Identifying agents able to induce the expression of the non-mutated spastin allele should represent an attractive therapeutic strategy in this disease.

Adenosine Triphosphatases↗

PubMed2026

Loss of function of the chromatin remodeling gene INO80D leads to neurogenic features of schizophrenia.

Schizophrenia has been linked to severely damaging de novo mutations in synaptic junction proteins, neurotransmitter receptors, transcription factors, and chromatin remodeling proteins. In a patient with schizophrenia in the absence of a family history of severe mental illness, we identified de novo nonsense mutation, INO80D p.Q568X, associated with both a truncated protein and partial nonsense-mediated decay. Three experiments were undertaken to evaluate the consequences of the mutation. 1) In neural stem cells (iNSCs) differentiated from WTC11 iPSCs, CRISPRi knockdown of INO80D led to downregulation of three subunits of the AMPA-glutamate receptor, of multiple genes mutant in schizophrenia, and of genes of synaptic function. 2) INO80D p.Q568X iNSCs and neurons differentiated from patient-derived induced pluripotent stem cells (iPSCs) had significantly lower expression of neurogenesis genes compared to patient-derived cells with the mutation corrected by CRISPR-Cas9 gene editing. Patient-derived INO80D p.Q568X neurons had significantly higher expression of cell division genes compared to lines with the mutation corrected, consistent with the possibility that some of these cells may be undergoing mitosis, which is not normal for neurons. 3) Finally, on microelectrode array (MEA) plates, WTC11-derived glutamatergic neurons with reduced expression of INO80D had more rapid firing rate and increased average network burst duration, both features of neurons derived from patients with neurodevelopmental disorders. Overall, these findings suggest that partial loss of INO80D function due to de novo mutation may have disrupted normal neurodevelopment and contributed to the schizophrenia of this patient.

Humans↗

PubMed1996

Interaction of a dimeric mitochondrial precursor with phospholipid vesicles: direct association of each subunit with the membrane is required for loss of functionality.

Binding of the precursor to mitochondrial aspartate aminotransferase to anionic phospholipid vesicles results in the loss of catalytic activity, apparently due to the inability of the bound protein to undergo the conformational transitions required for catalysis [A. Berezov, A. Iriarte, and M. Martinez-Carrion (1994) J. Biol. Chem. 269, 22222-22229]. Light scattering and electron microscopy analysis indicate that presequence-dependent binding of the precursor leads to extensive vesicle aggregation brought about by their cross-linking through interaction of each of the two presequences of this dimeric protein with separate vesicles. To evaluate the possible contribution of this aggregation to the properties of the bound protein, we analyzed the membrane interaction of a hybrid dimer containing a single presequence peptide. This dimer still binds to vesicles but does not cause aggregation. The properties of the bound hybrid are intermediate between those of the free and bound homo-precursor dimer with only the presequence-carrying subunit showing alterations in its structural and functional properties. These results indicate that the conformational perturbation of the mature moiety of lipid-bound precursor is caused by the direct interaction of each subunit with the membrane through its own N-terminal presequence peptide.

1,2-Dipalmitoylphosphatidylcholine↗

PubMed2005

Loss of function of retinoic acid in liver leads to steatohepatitis and liver tumor: A NASH animal model.

To explore the role of retinoic acid (RA) in liver, we developed transgenic mice expressing retinoic acid receptor alpha dominant negative form (RARE) in hepatocytes using by albumin promoter and enhancer. At 4 months of age, the RARE transgenic mice developed microvesicular steatosis and spotty focal necrosis. Mitochondrial beta-oxidation activity of fatty acids and expression of its related enzymes including VLCAD, LCAD and HCD were down-regulated. On the other hand, peroxisomal beta-oxidation and its related enzymes including AOX and BFE were up-regulated. Expression of CYP4a10, CYP4a12 and CYP4a14 was increased, suggesting that omega-oxidation of fatty acids in microsome was accelerated. In addition, formation of H(2)O(2) and 8-hydroxy-2'-deoxyguanosine was increased. After 12 months of age, these mice developed liver tumors which are hepatocellular carcinoma or adenoma. The incidence of tumor formation was increased with age. Expression of beta-catenin and cyclin D1 was enhanced, and TCF-4/beta-catenin complex was increased whereas RARalpha/beta-catenin complex was decreased. Feeding on high RA diet reversed histological and biochemical abnormalities, and inhibited occurrence of liver tumor. Taken together, hepatic loss of RA function leads to development of steatohepatitis and liver tumor and RA plays an important role in preventing hepatocarcinogenesis in association with fatty acid metabolism and Wnt signaling.

Journal Article↗